An Evaluation of the Causes and Outcomes of Haemophagocytic Lymphohistiocytosis in Sheffield Teaching Hospitals: 2016 to 2021

Background/Aims Haemophagocytic lymphiohistiocytosis (HLH) is a rare, underrecognised hyperinflammatory syndrome, characterised by immune dysregulation. Without treatment, the ensuing cytokine storm leads to high mortality. Secondary HLH (sHLH) is triggered by malignancy, infection, autoimmunity and medicines;treatment with immunosuppression is consensus- rather than evidence-based and extrapolated from primary HLH. Sheffield hosts a mature HLH multidisciplinary advisory group (MDAG). Here we evaluate the cause, treatment, requirement for critical care and mortality of people with HLH managed through the MDAG in a period including the coronavirus pandemic but prior to NHS England approval of anakinra (IL-1 antagonist) for HLH. Methods This retrospective evaluation (approved locally STH 10850) identified patients from MDAG records 1st October 2016 to 30th September 2021. Data from electronic/paper records was analysed using Microsoft Excel. Results HLH triggers were infection (viral 34%, bacterial 10%), haematological (35%), rheumatological (13%) and other (8%). Rheumatological causes were Still's disease (n=5);antiphospholipid syndrome (n=2);JO1 dermatomyositis (n=1);SLE (n=1);and rheumatoid arthritis (n=1). Other causes included unknown (n=3);combined systemic JIA and sickle cell crisis (n=1);medication (alemtuzumab) (n=1);and primary HLH (n=1). Overall mortality was 53% and highest in HLH with a haematological malignancy trigger (82%) Prior to the COVID19 pandemic (pre-March 2020), the commonest trigger of HLH was haematological malignancy (47%);after March 2020, the commonest trigger was infection (64%);COVID-19 explained 42% of cases. Mortality fell from 72% to 31%. Conclusion In this real-world series of people with HLH, mortality and critical care requirement was high. HLH triggers reflect published evidence as does poor prognosis in haematological malignancy-associated HLH. No-HLH associated with non-haematological malignancy was identified;we may need to improve MDAG reach into oncology. Seeming reduction in mortality following the COVID-19 pandemic may reflect increased recognition of COVID-19 induced hyperinflammation along with locallyagreed access to anakinra for COVID-19-induced HLH. The increase in infection related HLH cases since March 2020 is explained largely by COVID-19 cases. This has led to a relative reduction in cases related to haematological malignancy. HLH requires multidisciplinary management and better research to improve treatment. (Table Presented).

Early switch from cladribine to alemtuzumab in highly-active relapsing-remitting multiple sclerosis: A case report

Background Management of patients with multiple sclerosis (MS) and evidence of disease activity during treatment with cladribine tablets represents a challenging point. Objectives To report a patient with highly active multiple sclerosis (HAMS) who has been early switched from cladribine to alemtuzumab owing to tumultuous clinical and radiological activity Methods A single retrospective case report. Results. Treatment with alemtuzumab has led to a complete suppression of disease activity without any evidence of infections or acquired autoimmune diseases. Conclusion Our report suggests that an early switch from cladribine to alemtuzumab, may be safe and efficacious in selected HAMS cases.Copyright © 2022 The Authors

An unforeseen reality: Hemophagocytic lymphohistiocytosis following alemtuzumab treatment for a multiple sclerosis.

Alemtuzumab is a humanized monoclonal antibody indicated for treatment of highly active relapsing-remitting multiple sclerosis (HA-RRMS). It binds to CD52 antigen and produces a rapid and prolonged lymphocyte depletion followed by a different pattern of T and B cell repopulation. Among others, its adverse events are autoimmune diseases.In this article, we present a patient with HA-RRMS, who was subsequently treated with alemtuzumab and afterwards developed hemophagocytic lymphohistiocytosis (HLH). Albeit rarely, HLH can be triggered by alemtuzumab treatment.HLH can favourably respond to prompt immunosuppressant therapy.Multidisciplinary approach by a team consisting of a neurology, hematology and rheumatology specialist is needed to treat this potentially lethal condition.

Anti-CD52 Therapy for Multiple Sclerosis: An Update in the COVID Era.

CD52 is a small surface glycoprotein composed of 12 amino acids. CD52 is found mostly on the surface of mature immune cells, such as lymphocytes, monocytes, eosinophils, and dendritic cells, as well as the male genital tract: within the epididymis and on the surface of mature sperm. Low CD52 expression is also found in neutrophils. CD52 function is not fully understood, although experiments with anti-CD52 antibodies have shown that CD52 is essential for lymphocyte transendothelial migration and may contribute to costimulation of CD4+ T cells and T-cell activation and proliferation. Although knowledge about exact CD52 function is still poor, CD52 presence on the surface of a broad spectrum of immune cells makes it a therapeutic target, especially in immunomediated diseases, such as multiple sclerosis. In multiple sclerosis, alemtuzumab is registered for adult patients with the relapsing-remitting form of the disease defined by clinical and imaging features. Despite the high efficacy of the drug, the main issue is its safety. The main adverse effects of alemtuzumab are associated with drug infusion due to cytokine release and cytotoxic effects of antibodies associated with lymphocyte depletion, which leads to immunosuppression, and secondary autoimmunity that may be the effect of excessive B-cell repopulation and cancer. This review presents current knowledge on the drug's mechanism of action, efficacy and safety data from clinical trials, and real-world observations, including available though scarce data on using alemtuzumab in the COVID era.

In-depth characterization of long-term humoral and cellular immune responses to COVID-19m-RNA vaccination in multiple sclerosis patients treated with teriflunomide or alemtuzumab.

BACKGROUND: The impact of disease-modifying therapies on the efficacy to mount appropriate immune responses to COVID-19 vaccination in patients with multiple sclerosis (MS) is currently under investigation. OBJECTIVE: To characterize long-term humoral and cellular immunity in mRNA-COVID-19 MS vaccinees treated with teriflunomide or alemtuzumab. METHODS: We prospectively measured SARS-COV-2 IgG, memory B-cells specific for SARS-CoV-2 RBD, and memory T-cells secreting IFN-γ and/or IL-2, in MS patients vaccinated with BNT162b2-COVID-19 vaccine before, 1, 3 and 6 months after the second vaccine dose, and 3-6 months following vaccine booster. RESULTS: Patients were either untreated (N = 31, 21 females), under treatment with teriflunomide (N = 30, 23 females, median treatment duration 3.7 years, range 1.5-7.0 years), or under treatment with alemtuzumab (N = 12, 9 females, median time from last dosing 15.9 months, range 1.8-28.7 months). None of the patients had clinical SARS-CoV-2 or immune evidence for prior infection. Spike IgG titers were similar between untreated, teriflunomide and alemtuzumab treated MS patients both at 1 month (median 1320.7, 25-75 IQR 850.9-3152.8 vs. median 901.7, 25-75 IQR 618.5-1495.8, vs. median 1291.9, 25-75 IQR 590.8-2950.9, BAU/ml, respectively), at 3 months (median 1388.8, 25-75 1064.6-2347.6 vs. median 1164.3 25-75 IQR 726.4-1399.6, vs. median 837.2, 25-75 IQR 739.4-1868.5 BAU/ml, respectively), and at 6 months (median 437.0, 25-75 206.1-1161.3 vs. median 494.3, 25-75 IQR 214.6-716.5, vs. median 176.3, 25-75 IQR 72.3-328.8 BAU/ml, respectively) after the second vaccine dose. Specific SARS-CoV-2 memory B cells were detected in 41.9%, 40.0% and 41.7% of subjects at 1 month, in 32.3%, 43.3% and 25% at 3 months, and in 32.3%, 40.0%, 33.3% at 6 months following vaccination in untreated, teriflunomide treated and alemtuzumab treated MS patients, respectively. Specific SARS-CoV-2 memory T cells were found in 48.4%, 46.7% and 41.7 at 1 month, in 41.9%, 56.7% and 41.7% at 3 months, and in 38.7%, 50.0%, and 41.7% at 6 months, of untreated, teriflunomide-treated and alemtuzumab -treated MS patients, respectively. Administration of a third vaccine booster significantly increased both humoral and cellular responses in all patients. CONCLUSIONS: MS patients treated with teriflunomide or alemtuzumab achieved effective humoral and cellular immune responses up to 6 months following second COVID-19 vaccination. Immune responses were reinforced following the third vaccine booster.

Side effects, toxicity and ADRs of monoclonal antibodies in multiple organ systems

The review of publications on the safety profiles of three different immunosuppressants and immunomodulators (Alemtuzumab (ALZ), ipilimumab and nivolumab) published between January 2021 and April 2022 are being reported in this chapter. Alemtuzumab (ALZ), a humanized CD52 monoclonal antibody has been widely used in the treatment of Multiple sclerosis (MS). Nivolumab and ipilimumab are known as immune checkpoint inhibitors (ICIs), and both are commonly used in treatment of metastatic cancers. All three medications are still widely used by prescribers for these high-impact disease states, but post-study side effects are still being reported regularly. For example, the combination of ipilimumab and nivolumab is known to cause hypophysitis, which can manifest in different clinical presentations, levels of severity, and other comorbidities in patients. As another example, alemtuzumab has been linked to thyroid dysfunction, causing issues like Graves' hyperthyroidism. With the incidence of COVID-19, these medications have also resulted at putting patients at risk of contracting this new, viral disease, mainly due to immunosuppressive effects. Hence, knowing any recurrent and new adverse reactions are critical to provide the best combination of patient treatment while maintaining the integrity of drug monitoring. Additionally, recurrence of side effects can be prevented or appropriately prepared for during the course of treatment.

Challenges of COVID-19 in Rheumatic Autoimmune Diseases (RADs) Patients

Upon COVID-19 infection, age-specific mortality rates in RADs patients notably began from 35 years old, while in the uninfected population, it was from 55. COVID-19 associated rheumatic signs and symptoms are myalgia, fatigue, Kawasaki-like signs, and skin rashes mimicking vasculitides and pernio (chilblains) like lesions. So a variety of rheumatic diseases may mimic or be mimicked by COVID-19. Rheumatologic Treatments During COVID-19 Epidemic: Prednisone caused an increased hospitalization rate, significantly when the dose exceeded 10 mg per day. It is reasonable to reduce glucocorticoids gradually to 5 - 7.5 mg/day, but discontinuation during the pandemic is not recommended. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) reduce the risk of COVID-19 infection and the cytokine storm emerging in severe cases. Colchicine has reduced the mortality of COVID- 19 patients and the number of severe cases. Tapering or even discontinuing csDMARDs is suggested to recover immunity in severe cases, which may help rapidly eliminate the virus. Hydroxychloroquine is likely to increase survival in SLE patients, and it is not advisable to be discarded. Biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) may help reduce inflammatory cytokine storm under COVID-19 attack. Compared with RADs patients treated with CD20 monoclonal antibody rituximab or IL-17A antagonist secukinumab, patients receiving tumor necrosis factor (TNF) inhibitors etanercept and alemtuzumab or IL- 6 receptor antagonist tocilizumab may experience milder course. Applicable Laboratory Indicators: Elevation of ESR, CRP, ferritin, interleukin 6, and creatine kinase can be seen in COVID-19 and various rheumatic diseases. RADs related autoantibodies may present among non-RAD severe COVID- 19 cases. COVID-19 as a Risk Factor for Rheumatologic Diseases: Cases of Small vessel cardiac vasculitis/endothelium, immunoglobulin A (IgA) vasculitis in patients with Crohn disease, cutaneous vasculitis-like lesions, systemic arterial and venous thromboembolism including cryptogenic strokes and other vasculopathy features, systemic rheumatic diseases such as SLE, inflammatory arthritis, GCA, inflammatory myopathies, APS, Sjogren's syndrome, ANCA-associated vasculitides, seropositive rheumatoid arthritis, and Virus-associated or reactive arthritis and Crystal-related arthritis due to gout or calcium pyrophosphate disease has been reported. COVID-19, in the acute phase, may cause cytokine storm and severe inflammatory response;and in the chronic phase, patients become susceptible to autoinflammatory and autoimmune diseases. If a patient has signs and symptoms of rheumatic diseases after developing COVID-19, do not attribute these complaints entirely to COVID-19;consider starting a real dangerous rheumatic disorder.

EARLY, BUT NOT LATE USE OF REMDESVIR AND CONVALESCENT PLASMA REDUCES MORTALITY OF COVID 19 IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES - A STUDY OF KROHEM

Background: Patients with hematologic malignancies have a high risk of dying from COVID19 due to inability to mount humoral and cellular immune responses to the virus. Remdesvir is an inhibitor of viral RNA-polimerase. Some, but not all studies suggest it hastens recovery and reduces mortality in patients with COVID19. In a large randomized trial, convalescent plasma obtained from persons recovering from the infection was not proven to be useful in treatment of COVID19 in the general population, but other studies suggest it is useful in hematologic patients unable to produce antibodies against the virus. Recommendations on the use of these two drugs vary, some recommend its use only in severely immunocompromized individuals, some only in serious cases and some not at all. Reflecting these differences, the practice of using them varied between Croatian centers during the current pandemic. Aims: To analyze the effect of remdesvir and convalescent plasma on mortality in patients with hematologic malignancies by performing a matched-pair analysis. Methods: KroHem, the Croatian Cooperative Group for Hematologic Diseases, collected data on the outcome of patients with hematologic malignancies who became infected with SARS-COV2 while on concurrent systemic antineoplastic therapy during 2020 and 2021, before the appearance of the omicron strain. Patients treated with remdesvir and/or convalescent plasma were matched to those untreated according to age, disease type and antineoplastic therapy, factors found in our previous analyses to be related to outcome. Patients with Hodgkin lymphoma and myeloproliferative neoplasms were excluded, due to low risk of COVID19 mortality. Death during infection was considered as due to COVID19. Results: We identified 119 patients fulfilling the entry criteria. Three could not be matched, 2 with T-PLL treated with alemtuzumab and one with plasmablastic lymphoma and newly diagnosed HIV infection. All three died. In the remaining 116 patient pairs remdesvir significantly reduced the mortality: 36 out of 106 treated patients died, in comparison to 54 untreated (p=0.0207, McNemar's test). The effect of plasma was not significant: 26 of 73 treated patients died, in comparison to 33 untreated (p=0.2812). Therapy was substantially more effective in patients who received treatment within a week from symptom onset;11 of 58 patients treated with remdesvir died in comparison to 33 untreated (p<0.0001) and 8 out of 35 treated with plasma in comparison to 20 untreated (p=0.0095). Patients treated with remdesvir only had similar outcomes as those treated with remdesvir and plasma (15% vs. 19% respectively). (Figure Presented ) Summary/Conclusion: Our study suggests that patients with hematologic neoplasia, who are at a high risk of dying from COVID19, should receive treatment with remdesvir and convalescent plasma as soon as possible, resulting in a 2.5-3 times reduction in mortality. The effect of later treatment, if any, is less prominent.

Infectious issues of therapeutic monoclonal antibodies in multiple sclerosis and neuromyelitis optica spectrum disorders

Various effective monoclonal antibodies (mAbs) have been approved for both multiple sclerosis (MS) and anti-aquaporin-4-seropositive neuromyelitis optica spectrum disorders worldwide, including in Japan. As these newer mAbs have distinct modes of action that effectively suppress the recurrence of inflammation and slow disability progression, they can modulate and interfere with the protective immune response against pathogens, resulting in various infectious complications. Among various mAbs, natalizumab (NTZ) has the highest risk of causing progressive multifocal leukoencephalopathy (PML), a rare but fatal opportunistic brain infection caused by John Cunningham polyomavirus. Switching from NTZ to B-cell-depleting mAbs, such as ocrelizumab, is also a possible risk factor for PML development. Alemtuzumab carries the risk of reactivation of varicella-zoster virus (VZV);therefore, prophylactic acyclovir treatment is required. NTZ has also been associated with VZV reactivation. Eculizumab can cause severe meningococcal infection due to Neisseria meningitis, and vaccination prior to treatment induction is required. Attention to the reactivation of hepatitis B or Mycobacterium tuberculosis is also needed during mAb therapy. Additionally, in the era of severe acute respiratory syndrome coronavirus 2 infection (COVID-19), the risk for of developing severe COVID-19 may be associated with some mAbs, such as B-cell-depleting agents. Thorough understanding and mitigation strategies for infectious risks are essential.

Covid19 in Multiple Sclerosis Patients in Dubai: Observational Study

Objective: To assess symptoms, severity, outcome of Covid 9 in Multiple sclerosis patients ( including NeuroMyelitis Optica )and to assess the prognostic factors for severe Covid19 Background: Covid 19 pandemic came with its own challenges of novelty, lack of information uncertainty of treatment and its effect on chronic autoimmune diseases like Multiple sclerosis. The outcome of covid 19 with immunosuppressive and immunomodulatory treatment in multiple sclerosis was not known till this year. We share our observation of multiple sclerosis patients including neuromyelitis optics who contracted Covid 19 in Dubai UAE, during April 2020 to Sep 2021 in 2 major hospitals treating multiple sclerosis. Design/Methods: All Multiple sclerosis Patients following in Rashid hospital and Alzahra Hospital Neurology apartment who had Covid 19 were included in this observational study. Results: 55 MS patient with Covid 19 ( including 2 NMO) were studied. Age of the patients ranged from 19 to 58years. There were 39 females and 16 males. 43 were RRMS, 6 -SPMS,4- CIS, 1- PPMS and 2 NMOSD. 6 were on interferons, 2 on teriflunamide, 8 on dimethylfumarate, 12 on fingolimod, 3 on natalizumab, 1 on alemtuzumab, 1 on rituximab, 9 on cladribine, 12 on ocrelizumab and 1 on azathioprine. 47 had fever, 30 anosmia, 28 had fatigue and 42 had sorethroat and cough, 5/55 had pneumonia.39/55 had mild covid, 13/55 had moderate and 3 had severe covid 19. 3/55 needed ICU. There were 2 deaths, first with MS, EDSS 6.5 on ocrelizumab and second with NMO (EDSS 7.0)on rituximab Conclusions: The disease course and outcomes were mostly favorable with most patients not requiring hospitalization. A higher EDSS score, progressive disease, use of rituximab, and ocrelizumab(antiCD20 therapy) were associated with the mortality encountered. Age, sex, smoking history, and duration of MS were not independent risk factors for increased severity or adverse COVID-19 disease outcomes.

Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review and meta-analysis

Objective: To examine response of SARS-CoV-2 vaccination in patients with MS (pwMS) by a systematic review. Background: Varying responses to the SARS-CoV-2 vaccines have been reported in pwMS on disease modifying therapies (DMTs). We performed a meta-analysis and systematic review of pwMS and rates of immune response to SARS-CoV-2 vaccines by DMT and by vaccine type. Design/Methods: A systematic review was conducted for manuscripts from January 1, 2019 until October 1, 2021 by two independent reviewers (M.D. and G.G.). Search terms in PubMed, Google Scholar and Embase included “multiple sclerosis,” “SARS-CoV-2”, “Coronavirus-19”, “vaccines”, and “vaccinations.” Data from publications reporting on antibody or cellular vaccine response data in pwMS were included. Antibody response was defined as positive or negative, based upon assay cutoffs. Immune response to prior COVID infections were excluded. Descriptive statistics was performed using STATA. Results: We included 16 out of 589 articles and 186 healthy controls and 1,239 pwMS. Protective antibody responses were detected in 99% of healthy controls (184/186), 100% untreated pwMS (169/169), 99% pwMS on beta-interferons (79/80), and 100% pwMS on glatiramer acetate (39/39), dimethyl fumarate (116/116), natalizumab (127/127), alemtuzumab (19/19), and teriflunomide (72/72). Ninety-three percent of pwMS on cladribrine (69/74), 70% of sphingosine 1-phosphate modulators (S1PM) (108/155) and forty-six percent of pwMS on anti-CD20 treatments had an antibody response (177/388). PwMS on rituximab had a higher antibody response (23/37 = 62%) as compared to ocrelizumab (107/205 = 39%), with unknown anti-CD20 in 76. This difference may be attributable to the vaccination received (mRNA-1273 vs BNT162b2) as mRNA-1273 results in higher antibodies. However, 46/49 (94%) on anti-CD20 had T cell responses to SARS-CoV-2 vaccines. Conclusions: Varying rates of vaccine response are reported in pwMS. Humoral responses appear to be blunted in S1PM and anti-CD20 treatments;however, the majority develop cellular responses. Further investigation into how DMT affects immune response are needed.

A BRIEF SYNOPSIS OF MONOCLONAL ANTIBODY FOR THE TREATMENT OF VARIOUS GROUPS OF DISEASES.

Monoclonal antibodies (mAbs) are increasingly being prescribed to patients and investigated in the field of medicine and research. This class of medication is unique due to its ability to be engineered into targeting a specific receptor. Numerous studies and reviews have reported the efficacy, potency, and clinical usage of mAbs in the treatment of a variety of diseases ranging from autoimmune disorders to malignant cancers. However, very few publications classify and provide a brief synopsis of mAbs that includes their pharmacological profiles. mechanisms of action, uses, and side effects in a concise manner. Therefore, this review aims to classify the current mAbs drugs used in clinical practice according to system diseases by providing a brief summary for each of them. For example, regarding cardiovascular disorders, mAbs such as Abciximab, Bevacizumab, and Digoxin Immune Fab will be reviewed. Denosumab, used to treat musculoskeletal disorders, will be also discussed. In addition, mAbs such as Adalimumab, Eculizumab, Natalizumab used in autoimmune disorders and Alemtuzumab, Trastuzumab, Cetuximab, and Rituximab that are prescribed for tumors will be reviewed. Finally, we shall discuss two mAbs that are IL-6 antagonists, Tocilizumab and Siltuximab, which are in ongoing clinical trials as potential treatments of COVID-19. The mAbs have profound benefits against chronic and malignant conditions, and the overall purpose of this review is to illustrate the basic pharmacological profiles of mAbs that physicians may find useful in establishing their management protocols.

Efecto de los tratamientos de alta eficacia en pacientes con esclerosis múltiple sobre las respuestas humorales a las vacunas BNT162B2-COVID-19 O CORONAVAC

Introduction: Hasta la fecha existe escasa información sobre la eficacia de las vacunas contra SARS-CoV-2 en pacientes con esclerosis múltiple (pEM). Objetives: Nuestro objetivo fue evaluar la respuesta humoral a las vacunas contra SARS-CoV-2 en pEM bajo drogas modificadoras de la enfermedad (DME) de alta eficacia. Methods: Se midió IgG del SARS-CoV-2 utilizando serología basada en proteínas anti-spike y anti-nucleocápside basal y al mes de la segunda dosis de las vacunas BNT162b2-COVID-19 o CoronaVac. Se midió el valor absoluto (VA) del título de anticuerpos IgG anti-spike (IgGsp) y IgG anti-nucleocápside (IgGnc). Se definió respuesta humoral protectora (RHP) a títulos post vacuna > 1.0. Se compararon 4 grupos: pEM bajo tratamiento con cladribina, anti-CD20 (rituximab u ocrelizumab), alemtuzumab y se utilizó como grupo control a pEM sin tratamiento o bajo terapias inyectables (interferon o acetato de glatiramer). Results: Se incluyeron 16 (15%) y 90 (85%) pEM vacunados con BNT162b2-COVID-19 y CoronaVac respectivamente. Presentaron RHP IgGsp el 72.6%, 80%, 91.7%, 17.2% y 96.7%, en el total (N) de pacientes evaluados (106): grupo control (15), alemtuzumab (12), anti CD20 (29) y cladribina (30). Presentaron RHP IgGnc el 39.5%, 40%, 60%, 14.3% y 38.5% en el total de pacientes evaluados (38): grupo control (5), alemtuzumab (5), anti CD20 (7) y cladribina (13). Los VA de títulos de anticuerpos IgGsp fueron significativamente más bajos en los pEM en tratamiento con antiCD20 (7.42 ± 30.9) en comparación al grupo control (296.2 ± 640.9;p<0.01), cladribina (198.4 ± 399.9;p<0.01) y alemtuzumab (409.4 ± 717.8;p<0.01). Los pEM antiCD20 presentaron menor RHP IgGsp que cladribina (p<0.01) y alemtuzumab (p<0.01). No se encontraron diferencias significativas en el tiempo desde la última dosis entre los pEM antiCD20, cladribina y alemtuzumab (p=0.06). Hubo diferencias significativas entre menor edad y menor EDSS con RHP IgGsp (p=0.03 y p<0.01 respectivamente). Sin diferencias con el tipo de vacuna y tiempo desde la última. En el modelo de regresión logística sólo EDSS resultó ser un predictor significativo en RHP IgGsp (OR 0.50, IC95% 0.42 -0.83). Conclusions: Se encontró menor RHP IgGnc en comparación con IgGsp en todos los grupos evaluados. RHP IgGsp es menor en los pacientes con terapias anti CD20 y se desarrolla en terapias como cladribina, alemtuzumab y natalizumab, independiente de su última administración. Se requieren estudios de función de células T para los diferentes grupos, en especial antiCD20 para evaluar eficacia global de las vacunas.

Efecto del tratamiento biologico en pacientes con esclerosis

Introduction: En Ecuador se han reportado aproximadamente 500 mil casos con Covid 19 que ha producido impacto en pacientes con enfermedades crónicas inmunomediadas . La Esclerosis Múltiple (EM);se podria asociar a un mayor riesgo de complicaciones en pandemia, sin embargo últimos estudios incluyendo un meta análisis recientemente publicado han demostrado que éstos pacientes tienen menor riesgo de complicaciones y severidad de la enfermedad en relación a la población en general;esto debido al uso de agentes modificadores de la enfermedad que por su efecto inmunomodulador disminuyen niveles de citoquinas y mediadores pro inflamatorios que muestran un aparente efecto dual atenuando la severidad del C19 y aportando en el control de EM. Methods: Se realizó un estudio observacional, descriptivo y retrospectivo de una cohorte de 18 pacientes con diagnóstico de EM atendidos en el Hospital Metropolitano durante la pandemia por C19 desde 15 marzo 2020 a 16 agosto 2021 con el bjetivo de evaluar la severidad de C19 en pacientes con EM bajo tratamiento biológico, detallar el perfil clínico, demográfico y discapacidad ;comparar los efectos adversos (EA) del tratamiento biológico en EM y describir la cobertura de vacunación contra SARS COV 2 Results: La edad media fue de 36 años (19-58) con predominio en mujeres (83%);72% con EMRR y 28% EMSP. El 77.8% con discapacidad EDDS minima a leve y 11.1% de moderada a severa. 61% recibieron Ocrelizumab (EA: 36% rash), 22% con Rituximab (25% EA: dolor precordial) 17% con Alemtuzumab (EA: 100% Linfopenia severa y 66.6% diarrea). 3 pacientes (16%) se contagiaron de Covid, 2 bajo tratamiento con Ocrelizumab y 1 con Rituximab. No se registraron recurrencias de EM durante el seguimiento . El 70% recibieron vacunacion con Pfizer.

Abstracts from the 21st Australia and New Zealand Microcirculation Society Symposium

The proceedings contain 32 papers. The topics discussed include: characterization of pericyte changes in healthy and type 2 diabetic muscles;using a PDGFR-CREERT2 transgenic mouse line to deplete pericytes in the brain;megadose vitamin C: a new therapeutic to reverse renal microcirculatory dysfunction in sepsis and COVID-19;stroke accentuates age-dependent neutrophil impairment;biological control of adipose tissue repair - implications for healing of surgical wounds;circulating CCR6+ ILC levels are altered in alemtuzumab-treated multiple sclerosis patients;cladribine alters lymphocyte trans-endothelial migration via CD49D expression in multiple sclerosis patients;extracellular vesicles and mimetic technologies for theranostics;and novel phosphorescent stain for microvesicle penetration through brain microvascular endothelium.

Use of Cryopreserved Allogeneic PBSC Results in Delayed Engraftment and Increased Incidence of Poor Graft Function

Use of Cryopreserved Allogeneic PBSC Results in Delayed Engraftment And Increased Incidence of Poor Graft Function Introduction: During COVID Pandemic, national and international transplant centres agreed to use cryopreserve the donor PBSC as a safer option to deliver allogeneic transplants. Published data suggests that use of cryopreserved allogeneic PBSC is safe and comparable to use of fresh PBSC but cryopreservation of stem cells may lead to cell loss and hence efficacy. During COVID pandemic, use of cryopreserved allogeneic PBSC was adopted as policy on 01/06/2020. This look back analysis evaluates the impact of change in policy. Aims: Evaluate Engraftment time, compare with historical data, blood component support, and use of growth factors Methods and Materials: Data was collected from health records (paper and electronic) and laboratory records. Transplant features and engraftment kinetics were analysed. Results: Group A June 2020 to November 2020, 19 patients [M: 13;F: 6;median age: 50yr (range: 23-69)] who received cryopreserved allogeneic PBSC were compared to 35 patients [M:24;F:11;median age: 59yr (range: 21-71)] receiving fresh allogeneic PBSC for engraftment kinetics. There were no differences between two groups regarding underlying diagnosis (p=0.31), sex mismatch, CMV mismatch, blood group mismatch, reduced intensity conditioning [RIC](p=0.28), type of donor (p=0.98) or use of Alemtuzumab (p=0.88). Median infused Cell dose in group A was 5.3 (3.4-7.16) and in group B 4.9 (1.03-6.85), [p=0.11]. Neutrophil engraftment was significantly faster with fresh PBSC as compared to cryopreserved PBSC (16d vs. 25d, p=0.0025) predominantly with MUD (18d vs. 27d, p=0.009) and RIC (16d vs. 25d, p=0.009). Platelet engraftment to 25 was faster with fresh PBSC (13d vs. 20d, p=0.021) with delayed engraftment in MUD (20d vs. 13d, p=0.006) and RIC (23d vs. 13d, p=0.039). Day to engraftment per unit CD34 was shorter with fresh PBSC for neutrophils (median: 3.2, range: 2.0-7.7 vs. 5.3, range: 2.5-16.7;p=0.006) and platelets (median: 2.4, range: 1.7-25 vs. 3.8, range: 2.2-25;p=0.001) but only for MUD. This suggests 35-40% less efficiency with use of cryopreserved PBSC. There was no difference in the need for transfusion support [RBCs (6 units vs. 3 units, p=0.32);platelets (5 pools vs. 7 pools, p=0.33)]. G-CSF use was higher with cryopreserved PBSC in RIC (54% vs. 20%, p=0.031). Two patients experienced TRM before day 90 (3.7%). At day 90, 17/52 (32.7%) had cytopenia in one lineage and 8/52 (16%) had cytopenia in more than one lineage. Delayed engraftment was observed in 10 of 33 patients (30.3%) transplanted in 2020 and the only significant association was use of cryopreserved PBSC (0% vs. 53%, p=0.001). There was no difference in the incidence of aGVHD, hepatic VOD, microangiopathy and bacterial infections. Numbers are not sufficient to make disease specific comparisons. Conclusion: Cryopreserved PBSC result in delayed neutrophil and platelet engraftment predominantly with MUDS and RIC. Incidence of delayed engraftment and poor graft function is higher. Per unit CD34 dose, cryopreserved PBSC are 30-40% less efficient to achieve engraftment. Delayed engraftment with cryopreserved PBSC especially in MUD raises the possibility that time from harvest to cryopreservation contributes to reduced efficacy. Based on these findings it was decided to infuse higher CD34 dose (6-7x10

Clinical case of COVID-19 in a patient treated with alemtuzumab

The need to review the guidelines for the management of patients with multiple sclerosis using multiple sclerosis disease modifying drugs has become acute enough since the beginning of 2020 following the outbreak of the COVID-19 pandemic caused by a novel coronavirus SARS-CoV-2. Immunosuppressive drugs were also specifically addressed, as it is during administration of these drugs that the more severe course of COVID-19 disease was expected. Both the Russian and foreign teams published results of their research works. This article presents a retrospective analysis of the incidence rates of COVID-19 in patients with multiple sclerosis after selective immunosuppressive therapy with alemtuzumab and a clinical case when a patient was infected with coronavirus in the first days following the last infusion of the therapy course without clinical manifestations of the infectious disease. The author discusses the mechanisms underlying such a favourable outcome due to the CD52 lymphocyte depletion leading to the reduction of risks of developing hyperimmune reactions that underlie severe complications of COVID-19, and analyses previously published works of our foreign colleagues on the same theme. The review of the accumulated works and personal experience suggest that it is the CD52 lymphocyte depletion that makes it possible to avoid the cytokine storm and, as a result, the more severe course of COVID-19. Amidst the COVID-19 pandemic, during the prescription of multiple sclerosis disease modifying drugs, it should be borne in mind that patients should have access to all types of modern therapy and that the ben-efits should outweigh the sum of possible risks. © 2021, Remedium Group Ltd. All rights reserved.

CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis.

BACKGROUND: Ocrelizumab maintains B-cell depletion via six-monthly dosing. Whilst this controls relapsing multiple sclerosis, it also inhibits seroconversion following SARS-CoV-2 vaccination unlike that seen following alemtuzumab and cladribine treatment. Emerging reports suggest that 1-3% B-cell repopulation facilitates seroconversion after CD20-depletion. OBJECTIVE: To determine the frequency of B-cell repopulation levels during and after ocrelizumab treatment. METHODS: Relapse data, lymphocyte and CD19 B-cell numbers were obtained following requests to clinical trial data-repositories. Information was extracted from the phase II ocrelizumab extension (NCT00676715) trial and the phase III cladribine tablet (NCT00213135) and alemtuzumab (NCT00530348/NCT00548405) trials obtained clinical trial data requests RESULTS: Only 3-5% of people with MS exhibit 1% B-cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease-breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B-cells during treatment with either cladribine or alemtuzumab. CONCLUSIONS: Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. However, few people repopulate peripheral B-cells with standard ocrelizumab dosing. Controlled studies are warranted to examine a view that delaying the dosing interval by 3-6 months may allow more people to potentially seroconvert after vaccination.

Product review on MAbs (alemtuzumab and ocrelizumab) for the treatment of multiple sclerosis.

Traditionally, the management of active relapsing remitting MS was based on the, so-called, maintenance therapy, which is characterized by continuous treatment with particular disease modifying therapy (DMT), and a return of disease activity when the drug is discontinued. Another approach is characterized by a short treatment course of a DMT, which is hypothesized to act as an immune reconstitution therapy (IRT), with the potential to protect against relapses for years after a short course of treatment. Introduction of monoclonal antibodies in the treatment of MS has revolutionized MS treatment in the last decade. However, given the increasingly complex landscape of DMTs approved for MS, people with MS and neurologists are constantly faced with the question which DMT is the most appropriate for the given patient, a question we still do not have an answer to. In this product review, we will discuss the first DMT that acts as IRT, an anti-CD52 monoclonal antibody alemtuzumab and an anti CD20 monoclonal antibody, ocrelizumab that has the potential to act as an IRT, but is administered continuously. Special emphasis will be given on safety in the context of COVID-19 pandemics and vaccination strategies.

SARS-CoV-2 infection after alemtuzumab in a multiple sclerosis patient: milder disease symptoms in comparison with coinfected relatives: a case report and review of the literature.

Literature data reporting SARS-CoV-2 infection in multiple sclerosis (MS) patients recently treated with immunodepleting agents as cladribine and alemtuzumab are very limited. The relationship between iatrogenic immunodeficiency and risk related to SARS-CoV-2 infection and its severe complications is still not clear. Cautiously, the start of immunosuppressant drugs as alemtuzumab and cladribine during the current COVID-19 pandemic is not recommended unless treatment benefits significantly outweigh potential risks. We report the case of a 30-year-old female MS patient infected by SARS-CoV-2 virus 4 months after alemtuzumab II cycle, while she was still leukopenic and lymphopenic. She had no complications and also presented milder COVID-related signs and symptoms as compared to her coinfected relatives (father, mother and her partner). Anti-S1 and S2 SARS-CoV-2 antibodies, tested 1 month and a half after the infection, resulted positive. We review all cases reported in literature of SARS-CoV-2 infection in MS patients treated with alemtuzumab. None of them had complications or severe disease.