scholarly journals Uncharted waters: mesenchymal stem cell treatment for pediatric refractory rheumatic diseases; a single center case series

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Stephen C. Wong ◽  
Leah C. Medrano ◽  
Alice D. Hoftman ◽  
Olcay Y. Jones ◽  
Deborah K. McCurdy
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Adverse Events ◽  
Rheumatic Disease ◽  
Rheumatic Diseases ◽  
Tertiary Care ◽  
Case Series ◽  
Janus Kinase ◽  
Adjunctive Treatment ◽  
Infusion Therapy

Abstract Background With the advent of innovative therapies including biologics and Janus kinase inhibitors, children with rheumatic diseases are more likely to have improved outcomes. Despite these advances, some children do not respond, or they, or their parents fear adverse events and seek other alternatives. Increasingly, private companies are offering mesenchymal stem cells (MSC) as an alternative, which are described as natural therapies for rheumatic diseases, often insinuating them as a cure. MSC have immunomodulatory properties, and transplantation of these stem cells have been used to successfully treat immunologic conditions like graft-versus-host disease. Lately, MSC research in adult lupus has been encouraging, but the clinical trials are still underway and in most, MSC therapy is not a standalone treatment. This retrospective case series will highlight three cases of pediatric refractory autoimmune disease whose parents sought out and received MSC therapy as a self-decision without first seeking medical advice from our specialty. The three families felt that their children were improved and in two believed that their child was cured. MSC have the potential of beneficial immunomodulation and may be a powerful tool in the therapy of rheumatic disease, but well controlled clinical trials are necessary and should be designed and monitored by experts in childhood rheumatic disease. Case presentation Three children with three different rheumatic diseases; systemic lupus erythematosus, mixed connective tissue disease and juvenile idiopathic arthritis were under the care of pediatric rheumatology at a large, tertiary-care, teaching institution. Multiple non-biologic and biologic disease-modifying anti-rheumatic drugs failed to significantly decrease disease activity, and as a result, the families chose to undergo MSC therapy. After transplantation, all children improved per patient and parent report and tapered off conventional immunosuppressive drugs. No serious adverse events occurred in these three patients. Conclusion The three cases presented in this report reflect comparable beneficial outcomes and minimal risks published in adult studies. These were not controlled studies, however, and benefit was reported rather than documented. These cases suggest that MSC transplantation may prove a promising adjunctive treatment option; however, further research, development of standardized infusion therapy protocols, and well-designed monitored clinical trials are essential.

scholarly journals Uncharted waters: Mesenchymal stem cell Treatment for Pediatric Refractory Rheumatic Diseases; A Single Center Case Series

2021 ◽  
Author(s):  
Stephen Chee-Yung Wong ◽  
Leah C Medrano ◽  
Alice D Hoftman ◽  
Olcay Y Jones ◽  
Deborah K McCurdy
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Adverse Events ◽  
Rheumatic Disease ◽  
Rheumatic Diseases ◽  
Case Series ◽  
Janus Kinase

Abstract Background:With the advent of innovative therapies including biologics and Janus kinase inhibitors, children with rheumatic diseases are more likely to have improved outcomes. Yet, despite these advances, some children do not respond, or they, or their parents fear adverse events and seek other alternatives. Increasingly, there are private companies that offer mesenchymal stem cells (MSC) as an alternative and describe it as a more natural therapy for rheumatic diseases, often insinuating that there will be a cure. Mesenchymal stem cells have immunomodulatory properties, and transplantation of these stem cells have been used to successfully treat immunologic conditions like graft-versus-host disease. More recently, MSC research in adults with lupus has been encouraging, but the clinical trials are still underway and in most, mesenchymal stem cell therapy is not a standalone treatment. This retrospective case series will highlight three cases of children with refractory autoimmune disease whose parents sought out and received MSC therapy as a self-decision without first seeking medical advice from our specialty. In our cases, the three families felt that their children were improved and in two believed that their child was cured. Mesenchymal stem cells have the potential of beneficial immunomodulation and may be a powerful tool in the therapy of rheumatic disease, but well controlled clinical trials are necessary and should be designed and monitored by experts in childhood rheumatic disease. Case Presentation:Three children with three different rheumatic diseases; systemic lupus erythematosus, mixed connective tissue disease and juvenile idiopathic arthritis were under the care of pediatric rheumatology at a large, tertiary-care, teaching institution. Multiple non-biologic and biologic disease-modifying anti-rheumatic drugs failed to significantly decrease disease activity, and as a result, the families chose to undergo MSC therapy. After transplantation, all children improved per patient and parent report and tapered off conventional immunosuppressive drugs. No serious adverse events occurred in these three patients. Conclusion:The three cases presented in this study reflect comparable beneficial outcomes and minimal risks published in adult studies. These were not controlled studies, however, and benefit was reported rather than documented. These cases suggest that MSC transplantation may prove a promising adjunctive treatment option; however, further research, development of standardized infusion therapy protocols, and well-designed and monitored clinical trials are essential.

scholarly journals OP0097 LISTERIA MONOCYTOGENES. DESCRIPTION AND ANALYSIS OF CASES IN AN IMMUNODEPRESSED POPULATION BY RHEUMATIC DISEASES

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 53.2-54
Author(s):  
M. Lisbona Muñoz ◽  
P. León ◽  
G. Lopez Antequera ◽  
E. Rubio-Romero
Keyword(s):  
Listeria Monocytogenes ◽  
Rheumatic Disease ◽  
Pregnant Women ◽  
Rheumatic Diseases ◽  
Case Series ◽  
Similar Proportion ◽  
Neurological Manifestations ◽  
Biological Dmards ◽  
Parametric Data ◽  
The Impact

Background:Listeria monocytogenes is a gram-positive bacteria that cause the invasive disease listeriosis. Human clinical syndromes are infrequent, mostly appearing in immunosuppressed individuals, newborns, the elderly, pregnant women, and occasionally healthy patients.Objectives:We describe and analyze Listeria-related demographics and clinical features to determine the predisposing conditions for severe infections in an immunodepressed population by rheumatic diseases.Methods:Descriptive Observational Study. A retrospective analysis of 143 patients were performed affected by listeriosis, with positive isolation of Listeria monocytogenes from blood, treated in the H.U. Virgen del Rocío (Seville- Spain) between 2003-2019. Of them 9 were rheumatic patients. The type of clinical manifestation was analyzed, paying special attention to the characteristics associated with patients with neurological complications or unfavorable outcome (death and / or abortion in pregnant women), immunosuppression (associated with cancer or rheumatic disease) was assessed as independent variables, chronic diseases (Hypertension, Diabetes Mellitus, dyslipidemia, COPD, Renal Insufficiency and Ischemic Heart Disease) as well as other baseline characteristics of the patient. (age, sex, pregnancy) and their toxic habits (tobacco and alcohol).Results:The sample includes a similar proportion of men (70 cases) and women (73 cases), of all ages. Of the total patients, most (85%) required hospital admission, with a duration median (non-parametric data) of 11 days. 78% of the cases admitted showed a favorable evolution. However, 15.4% resulted in death and 5.6% in abortion. This percentage of abortions represented 29% of the total pregnant women admitted Of all the patients admitted, a third (33%) were immunocompromised, including patiets with cancer (79%) and rheumatic diseases (21%). Include lupus (33%), RA (22%), APs (11%), polymyalgia rheumatica (11%), panuveitis (11%) and ANCA vasculitis MPO specificity (11%). All of them required admission although the majority showed a favorable evolution, except one of the patient. which resulted in death, in which case in addition to lupus he presented with prostate cancer. Regarding the baseline treatment of these patients, 7 underwent treatment with synthetic DMARDs and three with biological DMARDs (1 Adalimumab, 1 Infliximab and 1 Rituximab) As a result of the listeria infection, most of them had fever or digestive symptoms and two of they experienced neurological manifestations (meningoencephalitis) None of these last two (with lupus and RA) had biological DMARDs.Conclusion:Listeriosis is an uncommon but potentially serious infection usually in older people, pregnant women and immunocompromised patients. In our sample, 33% of the patients were immunocompromised. Of the 9 patients. affected by listeria with rheumatic disease we find a death for meningoencephalitis. Given the impact of this infection in immunosuppressed patients should pay attention in our patients with fever and neurological manifestations.Reference:[1]Eleftherios Mylonakis et al. A Case Series and Review of 222 Cases. Medicine 2002; 81: 260-269.[2]Alcoba Lez M et al.Meningitis por Listeria monocytogenes en el adulto en España. Presentación de 10 casos y revisión de la literatura. Rev Clin Esp 2002; 202 (12): 638-643.[3]Eleftherios Mylonakis et al. Central Nervous Sistem Infection with Listeria monocytogenes. 33 Years’ Experience at a General Hospital and Review of 776 Episodes from tha Literature. Medicine 1998; 77: 313-336.Disclosure of Interests:None declared

scholarly journals Programmed cell death-1 and programmed cell death ligand-1 antibodies-induced dysthyroidism

2018 ◽  
Vol 7 (5) ◽  
pp. R196-R211 ◽  
Author(s):  
Jaafar Jaafar ◽  
Eugenio Fernandez ◽  
Heba Alwan ◽  
Jacques Philippe
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Adverse Events ◽  
English Language ◽  
Case Series ◽  
Immune Checkpoints ◽  
Pubmed Database ◽  
Programmed Cell Death 1 ◽  
Time To Onset

Background Monoclonal antibodies blocking the programmed cell death-1 (PD-1) or its ligand (PD-L1) are a group of immune checkpoints inhibitors (ICIs) with proven antitumor efficacy. However, their use is complicated by immune-related adverse events (irAEs), including endocrine adverse events (eAEs). Purpose We review the incidence, time to onset and resolution rate of dysthyroidism induced by PD-1/PD-L1 Ab, and the clinical, biological and radiological findings. We aim to discuss the potential mechanisms of PD-1/PD-L1 Ab-induced dysthyroidism, and to propose a management algorithm. Methods We performed a literature search of available clinical trials regarding PD-1/PD-L1 Ab in the PubMed database. We selected all English language clinical trials that included at least 100 patients. We also present selected case series or reports, retrospective studies and reviews related to this issue. Findings In patients treated with PD-1 Ab, hypothyroidism occurred in 2–10.1% and hyperthyroidism occurred in 0.9–7.8%. When thyroiditis was reported separately, it occurred in 0.34–2.6%. Higher rates were reported when PD-1 Ab were associated with other ICI or chemotherapy. The median time to onset of hyperthyroidism and hypothyroidism after PD-1 Ab initiation was 23–45 days and 2–3.5 months, respectively. Regarding PD-L1 Ab, hypothyroidism occurred in 0–10% and hyperthyroidism in 0.5–2% of treated patients. The average time to onset of dysthyroidism after PD-L1 Ab was variable and ranged from 1 day after treatment initiation to 31 months. Conclusion Dysthyroidism occurs in up to 10% of patients treated with PD-1/PD-L1 Ab. Hypothyroidism and reversible destructive thyroiditis are the most frequent endocrine adverse events (eAE) in PD-1/PD-L1 treated patients. Immune and non-immune mechanisms are potentially involved, independently of the presence of thyroid antibodies.

scholarly journals Hydroxychloroquine in Patients with Rheumatic Disease Complicated by COVID-19: Clarifying Target Exposures and the Need for Clinical Trials

2020 ◽  
Vol 47 (9) ◽  
pp. 1424-1430 ◽  
Author(s):  
Stephen J. Balevic ◽  
Christoph P. Hornik ◽  
Thomas P. Green ◽  
Megan E.B. Clowse ◽  
Daniel Gonzalez ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antiviral Activity ◽  
Rheumatic Disease ◽  
Rheumatic Diseases ◽  
Pharmacokinetic Model ◽  
Therapeutic Window ◽  
Total Serum ◽  
Viral Inhibition ◽  
Target Exposure

Objective.To characterize hydroxychloroquine (HCQ) exposure in patients with rheumatic disease receiving longterm HCQ compared to target concentrations with reported antiviral activity against the coronavirus disease 2019 caused by SARS-CoV-2 (COVID-19).Method.We evaluated total HCQ concentrations in serum and plasma from published literature values, frozen serum samples from a pediatric systemic lupus erythematosus trial, and simulated concentrations using a published pharmacokinetic model during pregnancy. For each source, we compared observed or predicted HCQ concentrations to target concentrations with reported antiviral activity against SARS-CoV-2.Results.The average total serum/plasma HCQ concentrations were below the lowest SARS-CoV-2 target of 0.48 mg/l in all studies. Assuming the highest antiviral target exposure (total plasma concentration of 4.1 mg/l), all studies had about one-tenth the necessary concentration for in vitro viral inhibition. Pharmacokinetic model simulations confirmed that pregnant adults receiving common dosing for rheumatic diseases did not achieve target exposures; however, the models predict that a dosage of 600 mg once a day during pregnancy would obtain the lowest median target exposure for most patients after the first dose.Conclusion.We found that the average patient receiving treatment with HCQ for rheumatic diseases, including children and non-pregnant/pregnant adults, are unlikely to achieve total serum or plasma concentrations shown to inhibit SARS-CoV-2 in vitro. Nevertheless, patients receiving HCQ long term may have tissue concentrations far exceeding that of serum/plasma. Because the therapeutic window for HCQ in the setting of SARS-CoV-2 is unknown, well-designed clinical trials that include patients with rheumatic disease are urgently needed to characterize the efficacy, safety, and target exposures for HCQ.

scholarly journals Repurposing of drugs for Covid-19: a systematic review and meta-analysis

2020 ◽  
Author(s):  
Pinky Kotecha ◽  
Alexander Light ◽  
Enrico Checcucci ◽  
Daniele Amparore ◽  
Cristian Fiori ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Adverse Events ◽  
Clinical Improvement ◽  
Case Reports ◽  
Meta Analysis ◽  
Case Series ◽  
Cochrane Library ◽  
Control Group ◽  
Significant Difference

AbstractObjectiveThe aim of this systematic review is to evaluate the data currently available regarding the repurposing of different drugs for Covid-19 treatment. Participants with suspected or diagnosed Covid-19 will be included. The interventions being considered are drugs being repurposed, and comparators will include standard of care treatment or placebo.MethodsWe searched Ovid-MEDLINE, EMBASE, Cochrane library, clinical trial registration site in the UK(NIHR), Europe (clinicaltrialsregister.eu), US (ClinicalTrials.gov) and internationally (isrctn.com), and reviewed the reference lists of articles for eligible articles published up to April 22, 2020. All studies in English that evaluated the efficacy of the listed drugs were included. Cochrane RoB 2.0 and ROBINS-I tool were used to assess study quality. This systematic review adheres to the PRISMA guidelines. The protocol is available at PROSPERO (CRD42020180915).ResultsFrom 708 identified studies or clinical trials, 16 studies and 16 case reports met our eligibility criteria. Of these, 6 were randomized controlled trials (763 patients), 7 cohort studies (321 patients) and 3 case series (191 patients). Chloroquine (CQ) had a 100% discharge rate compared to 50% with lopinavir-ritonavir at day 14, however a trial has recommended against a high dosage due to cardiotoxic events. Hydroxychloroquine (HCQ) has shown no significant improvement in negative seroconversion rate which is also seen in our meta-analysis (p=0.68). Adverse events with HCQ have a significant difference compared to the control group (p=0.001). Lopinavir-ritonavir has shown no improvement in time to clinical improvement which is seen in our meta-analyses (p=0.1). Remdesivir has shown no significant improvement in time to clinical improvement but this trial had insufficient power.DiscussionDue to the paucity in evidence, it is difficult to establish the efficacy of these drugs in the treatment of Covid-19 as currently there is no significant clinical effectiveness of the repurposed drugs. Further large clinical trials are required to achieve more reliable findings. A risk-benefit analysis is required on an individual basis to weigh out the potential improvement in clinical outcome and viral load reduction compared to the risks of the adverse events. (1-16)

scholarly journals Outcomes of COVID-19 in a cohort of pediatric patients with rheumatic diseases

2021 ◽  
Author(s):  
Diana Sofia Villacis-Nunez ◽  
Christina A. Rostad ◽  
Kelly Rouster-Stevens ◽  
Arezou Khosroshahi ◽  
Shanmuganathan Chandrakasan ◽  
...  
Keyword(s):  
Rheumatic Disease ◽  
Rheumatic Diseases ◽  
Pediatric Patients ◽  
Univariate Analysis ◽  
Case Series ◽  
Hospitalized Patients ◽  
High Dose ◽  
High Dose Corticosteroid ◽  
Severe Immunosuppression ◽  
Dose Corticosteroid

Abstract Background There are few reports of COVID-19 in pediatric patients with rheumatic diseases. This study describes the clinical presentation and outcomes of COVID-19 in this population. Methods We analyzed a single-center case series of pediatric patients with rheumatic diseases and laboratory-confirmed COVID-19. Demographic, baseline and COVID-19 associated clinical features were compared between ambulatory and hospitalized patients using univariate analysis. Results Forty cases were identified: 32 (80%) in the ambulatory group and 8 (20%) hospitalized. Older age (median age 18 years vs 16 years; p = 0.01) and African American race (OR 8.42; 95% CI [1.20-101.69]; p = 0.01) predominated in hospitalized patients. Systemic lupus erythematosus (OR 6.77; 95% CI [1.01–56.71]; p = 0.02), medium/high-dose corticosteroid use (OR 10.62; 95% CI [1.46–99.57]; p = 0.008), mycophenolate use (OR 11.91; 95% CI [1.64-149.35]; p = 0.005), and severe immunosuppression (OR 16.83; 95% CI [1.74-861.43]; p = 0.004) were associated with increased odds of hospitalization. Patients with fever (OR 11.91; 95% CI [1.64-149.35]; p = 0.004), dyspnea (OR 16.51; CI [1.10-998.37]; p = 0.02), and myalgias (OR 13.40; 95% CI [1.43-194.56)]; p = 0.009) were more commonly encountered in the hospitalized group. Rheumatic disease flares were almost exclusive to hospitalized patients (OR 42.13; 95% CI [3.40-2463.87]; p < 0.001).. All patients recovered. Conclusions Medium/high-dose corticosteroid use, mycophenolate use, and severe immunosuppression were risk factors for hospitalization. Fever, dyspnea and myalgias were high-risk symptoms. The type of rheumatic disease, as well as disease flare could be contributing factors to the need for hospitalization.

scholarly journals Clinical Application of Mesenchymal Stem Cells and Novel Supportive Therapies for Oral Bone Regeneration

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Miguel Padial-Molina ◽  
Francisco O’Valle ◽  
Alejandro Lanis ◽  
Francisco Mesa ◽  
David M. Dohan Ehrenfest ◽  
...  
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
Bone Regeneration ◽  
Case Reports ◽  
Periodontal Regeneration ◽  
Case Series ◽  
Bioactive Molecules ◽  
Alloplastic Materials ◽  
Clinical Scenarios

Bone regeneration is often needed prior to dental implant treatment due to the lack of adequate quantity and quality of the bone after infectious diseases, trauma, tumor, or congenital conditions. In these situations, cell transplantation technologies may help to overcome the limitations of autografts, xenografts, allografts, and alloplastic materials. A database search was conducted to include human clinical trials (randomized or controlled) and case reports/series describing the clinical use of mesenchymal stem cells (MSCs) in the oral cavity for bone regeneration only specifically excluding periodontal regeneration. Additionally, novel advances in related technologies are also described. 190 records were identified. 51 articles were selected for full-text assessment, and only 28 met the inclusion criteria: 9 case series, 10 case reports, and 9 randomized controlled clinical trials. Collectively, they evaluate the use of MSCs in a total of 290 patients in 342 interventions. The current published literature is very diverse in methodology and measurement of outcomes. Moreover, the clinical significance is limited. Therefore, the use of these techniques should be further studied in more challenging clinical scenarios with well-designed and standardized RCTs, potentially in combination with new scaffolding techniques and bioactive molecules to improve the final outcomes.

scholarly journals POS1194 THE EFFECT OF SARS-COV-2 ON THE COURSE AND THE TREATMENT OF RHEUMATIC INFLAMMATORY DISEASES. EXPERIENCE FORM THE NORTHWESTERN GREECE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 879.1-879
Author(s):  
E. Pelechas ◽  
E. Kaltsonoudis ◽  
M. Migos ◽  
P. Karagianni ◽  
A. Kavvadias ◽  
...  
Keyword(s):  
Rheumatic Disease ◽  
Hospital Stay ◽  
Rheumatic Diseases ◽  
Inflammatory Diseases ◽  
Immunosuppressive Treatment ◽  
Janus Kinase ◽  
Inflammatory Rheumatic Diseases ◽  
Low Grade ◽  
Low Oxygen ◽  
Mild Disease

Background:COVID-19 has been shown to significantly affect the vulnerable population [1,2]. Among them, patients suffering from inflammatory rheumatic diseases, and especially the immunosuppressed [3].Objectives:to assess the effect of SARS-CoV-2 on the course and the treatment of rheumatic inflammatory diseases.Methods:from February to December 2020, 46 patients with inflammatory rheumatic diseases were included (32 female) that got infected with the SARS-CoV-2. Mean age was 65 years old, 17 were smokers, 12 had arterial hypertension, 8 diabetes mellitus, and 3 hypothyroidism. Most of them had their comorbidities well-controlled and their rheumatic disease was in remission. More specifically, 24 patients had rheumatoid arthritis, 13 psoriatic arthritis, and 9 ankylosing spondylitis. All patients were under treatment with conventional synthetic (cs) and/or biological (b) disease-modifying anti-rheumatic drugs (DMARDs), while 7 of them were also on treatment with glucocorticoids (GC) (<5mg/day). Twenty-eight patients were on tumor necrosis alpha (TNF-α) inhibitors (19 as monotherapy), 4 on anti- interleukin (IL)-6 monotherapy, 3 on Janus Kinase (JAK) inhibitors plus on low dose methotrexate (MTX), and the rest (11 patients) were on a csDMARD with or without GCs.Results:positive patients with the SARS-CoV-2, instructed to discontinue their immunosuppressive treatment, except GCs that were adjusted for their disease. Most patients (37 out of 46) had a mild disease course and their symptomatology was nothing more than a simple flu-like syndrome. Furthermore, on 9 of them olfactory dysfunction and gastrointestinal manifestations as well as low grade fever were noted but without the need of a hospital admission. On the other hand, only 5 patients needed hospitalization (2 on MTX monotherapy and 3 on combination therapy) due to dyspnea with low oxygen saturation (hypoxemia) and high fever. From those 5, 3 had a short in-hospital stay, while 2 developed pneumonia and a longer in-hospital stay was required in order to get the appropriate treatment. None of the patients did not require an intensive care unit admission. Finally, in 14 patients that got infected from February to May 2020, viral antibodies had been measured. All patients had high titres of IgG antibodies in their serum for as long as six months after their infection. Of note, none of the infected patients were smokers.Conclusion:patients with rheumatic diseases that are in remission using low doses of GCs and DMARDs, have almost the same chances with the general population to have a serious course of their infection with the SARS-Cov-2. In addition, in these patients, the immune response appears to be adequate, both in the production and maintenance of antibodies, which appear to be maintained for at least 6 months after infection.References:[1]Patel JA, Nielsen FBH, Badiani AA, Assi S, Unadkat VA, Patel B, et al. Poverty, inequality and COVID-19: the forgotten vulnerable. Public Health. 2020;183:110-111. Doi: 10.1016/j.puhe.2020.05.006.[2]Poteat T, Millet GA, Nelson LE, Beyrer C. Understanding COVID-19 risks and vulnerabilities among black communities in America: the lethal force of syndemics. Ann Epidemiol. 2020;47:1-3. Doi: 10.1016/j.annepidem.2020.05.004.[3]Gianfrancesco MA, Hyrich KL, Gossec L, Strangfeld A, Carmona L, Mateus EF, et al. Rheumatic disease and COVID-19: initial data from the COVID-19 Global Rheumatology Alliance provider registries. Lancet Rheumatol. 2020;2(5):e250-e253. Doi: 10.1016/S2665-9913(20)30095-3.Disclosure of Interests:None declared.

scholarly journals Efficacy and Safety of Voxelotor in Sickle Cell Disease: A Systematic Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Muhammad Ashar Ali ◽  
Anam Khan ◽  
Sana Irfan Khan ◽  
Sobia Aamir ◽  
Saad Ur Rahman ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Sickle Cell Disease ◽  
Adverse Events ◽  
Sickle Cell ◽  
Reticulocyte Count ◽  
Case Series ◽  
Efficacy And Safety ◽  
Cell Disease ◽  
Grade 3

Introduction: Sickle cell disease (SCD) is caused by mutation of beta-globin chain alleles, with the involvement of at least one sickle mutation. Sickling of red cells leads to hemolytic anemia, vaso-occlusions, and inflammation. Voxelotor (GBT440) is a hemoglobin modulator that prevents polymerization by increasing the affinity of hemoglobin with oxygen. We performed a systematic review to evaluate the efficacy and safety of voxelotor in SCD patients. Methods: PRISMA guidelines were followed to perform the literature search and selection of articles for this systematic review. A search was performed using databases including PubMed, Cochrane, Web of Science, Embase, and clinicaltrials.gov. We used the following keywords, "Voxelotor" OR "Benzaldehydes" OR "GBT440" AND "Sickle Cell Anemia" from the inception of literature till 04/25/2020. Out of 475 articles, we screened and included three clinical trials and a case series measuring the efficacy (i-e, change in Hemoglobin (Hb), Hb modification, etc.) and safety (adverse events) in clinical terms (N=359). We excluded case reports, pre-clinical studies, review articles, and meta-analysis. RESULTS: We included data on 359 patients, with 12-67 years of age. In Blyden et al. 2018, authors presented a case series of 7 patients with advanced SCD treated with 700 mg-1500 mg voxelotor. With treatment, vaso-occlusive episodes related hospitalizations decreased by 67%, hemoglobin levels, and markers of hemolysis improved in all patients. Authors in Hutchaleelaha et al. 2019 randomly assigned 24 participants to a once-daily dose of 900 mg, 600 mg, 300 mg voxelotor, and placebo for 15 days. With treatment, hemoglobin modification was maximum in the 900 mg voxelotor group. Headache and diarrhea were the only adverse events related to voxelotor treatment. No grade 3 adverse events were reported. In phase I/II trial by Howard et al. 2019, (n=54) 38 patients were followed for 28 days, and 16 patients were followed for &gt;90 days. The compliance for study drug was 91%. In the 28-day cohort, treatment with 1000 mg of voxelotor showed maximum improvement in hemoglobin level, reticulocyte count, and unconjugated bilirubin. In &gt;90-day cohort, the improvement in hemoglobin, unconjugated bilirubin, and reticulocyte count were statistically significant in favor of 900 mg voxelotor treatment as compared to placebo (p&lt;0.05). LDH showed variability with treatment. Vaso-occlusive episodes seen in voxelotor groups were reported when the treatment was on hold or after the last dose. No grade ≥3 adverse events were reported. In a randomized placebo-controlled phase III clinical trial by Vichinsky et al. 2019, two doses of voxelotor 1500 mg (N=90) and 900 mg (N=92) were compared with placebo (N=92). 12-65 years old SCD patients were followed for 24 weeks. After treatment, improvement in hemoglobin was statistically significant in favor of 1500 mg voxelotor vs. placebo. Moreover, markers of hemolysis, reticulocyte count, and indirect bilirubin levels were also significantly improved in favor of 1500mg voxelotor treatment vs. placebo. The incidence of vaso-occlusive crisis episodes was similar in 1500 mg, 700 mg, and placebo groups (p&gt;0.05). Treatment-related adverse events were seen in 94%, 93%, and 89% of participants in 1500mg, 700mg, and placebo groups, respectively. (Table 1) There are 6 ongoing clinical trials registered on clinicaltrials.gov (n=665) to determine the efficacy and safety of high doses of voxelotor and its use in children below 12 years. (Table 2) Conclusion: Voxelotor has an acceptable safety profile in sickle cell disease patients of 12 years or older. Voxelotor has shown a dose-dependent improvement in hemoglobin levels and markers of hemolysis, which is associated with a reduction in end-organ damage. Moreover, the increase in hemoglobin was not associated with an increase in vaso-occlusive crisis episodes, in contrast to the other hemoglobin modulator (senicapoc). Additional large prospective multicenter randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

scholarly journals Stem Cells as a Model of Study of SARS-CoV-2 and COVID-19: A Systematic Review of the Literature

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
María Verónica Cuevas-Gonzalez ◽  
Álvaro Garcia-Perez ◽  
Álvaro Edgar Gonzalez-Aragon Pineda ◽  
León Francisco Espinosa-Cristobal ◽  
Alejandro Donohue-Cornejo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Stem Cell ◽  
Clinical Studies ◽  
Case Series ◽  
In Vitro Studies ◽  
In Vivo Studies

Background. The SARS-CoV-2 virus is the cause of the latest pandemic of the 21st century; it is responsible for the development of COVID-19. Within the multiple study models for both the biology and the treatment of SARS-CoV-2, the use of stem cells has been proposed because of their ability to increase the immune response and to repair tissue. Therefore, the objective of this review is to evaluate the role of stem cells against SARS-CoV-2 and COVID-19 in order to identify their potential as a study model and as a possible therapeutic source against tissue damage caused by this virus. Therefore, the following research question was established: What is the role of stem cells in the study of SARS-CoV-2 and the treatment of COVID-19? Materials and Methods. A search was carried out in the electronic databases of PUBMED, Scopus, and ScienceDirect. The following keywords were used: “SARS-CoV-2,” “COVID-19,” and “STEM CELL,” plus independent search strategies with the Boolean operators “OR” and “AND.” The identified reports were those whose main objective was the study of stem cells in relation to SARS-CoV-2 or COVID-19. For the development of this study, the following inclusion criteria were taken into account: studies whose main objective was the study of stem cells in relation to SARS-CoV-2 or COVID-19 and clinical case studies, case reports, clinical trials, pilot studies, in vitro, or in vivo studies. For assessment of the risk of bias for in vitro studies, the SciRAP tool was used. The data collected for each type of study, clinical or in vitro, were analyzed with descriptive statistics using the SPSS V.22 program. Results. Of the total of studies included ( n = 39 ), 22 corresponded to in vitro investigations and 17 to human studies (clinical cases ( n = 9 ), case series ( n = 2 ), pilot clinical trials ( n = 5 ), clinical trials ( n = 1 )). In vitro studies that induced pluripotent stem cells were the most used ( n = 12 ), and in clinical studies, the umbilical stem cells derived were the most reported ( n = 11 ). The mean age of the study subjects was 58.3 years. After the application of stem cell therapy, the follow-up period was 8 days minimum and 90 days maximum. Discussion. The mechanism by which the virus enters the cell is through protein “S,” located on the surface of the membrane, by recognizing the ACE2 receptor located on the target cell. The evidence that the expression of ACE2 and TMPRSS2 in stem cells indicates that stem cells from bone marrow and amniotic fluid have very little expression. This shows that stem cell has a low risk of infection with SARS-CoV-2. Conclusion. The use of stem cells is a highly relevant therapeutic option. It has been shown in both in vitro studies and clinical trials that it counteracts the excessive secretion of cytokines. There are even more studies that focus on long-term follow-up; thus, the potential for major side effects can be analyzed more clearly. Finally, the ethical use of stem cells from fetal or infant origin needs to be regulated. The study was registered in PROSPERO (no. CRD42021229038). The limitations of the study were because of the methodology employed, the sample was not very large, and the follow-up period of the clinical studies was relatively short.

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