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The Journal of Clinical Endocrinology... Jan 2024Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical...
OBJECTIVE
Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical characteristics of alemtuzumab-induced GD.
METHODS
Retrospective follow-up study of MS patients treated with alemtuzumab from 2014 to 2020, including clinical course of GD, pregnancy outcome, and thyroid eye disease (TED).
RESULTS
We enrolled 183 of 203 patients (90%, 68% women) treated with alemtuzumab at 4 hospitals in Norway. Seventy-five (41%) developed thyroid dysfunction, of whom 58 (77%) had GD. Median time from the first dose of alemtuzumab to GD diagnosis was 25 months (range, 0-64). Twenty-four of 58 GD patients (41%) had alternating phases of hyper- and hypothyroidism. Thyrotropin receptor antibodies became undetectable in 23 of 58 (40%) and they could discontinue antithyroid drug treatment after a median of 22 (range, 2-58) months. Conversely, 26 (44%) had active disease during a median follow-up of 39 months (range, 11-72). Two patients (3%) received definitive treatment with radioiodine, 6 (10%) with thyroidectomy. Nine developed TED (16%), 7 had mild and 2 moderate to severe disease. Four patients completed pregnancy, all without maternal or fetal complications. Patients who developed GD had a lower frequency of new MS relapses and MRI lesions than those without.
CONCLUSION
GD is a very common complication of alemtuzumab treatment and is characterized by alternating hyper- and hypothyroidism. Both remission rates and the prevalence of TED were lower than those reported for conventional GD. Pregnancies were uncomplicated and GD was associated with a lower risk of subsequent MS activity.
Topics: Humans; Female; Pregnancy; Male; Alemtuzumab; Retrospective Studies; Iodine Radioisotopes; Prevalence; Follow-Up Studies; Graves Disease; Multiple Sclerosis; Hypothyroidism; Graves Ophthalmopathy; Risk Factors
PubMed: 37708353
DOI: 10.1210/clinem/dgad540 -
Problemy Endokrinologii Jun 2023Multiple sclerosis (MS) is a severe chronic autoimmune demyelinating disease of the central nervous system, mediated by Th1/Th17 lymphocytes as well as B lymphocytes,...
Multiple sclerosis (MS) is a severe chronic autoimmune demyelinating disease of the central nervous system, mediated by Th1/Th17 lymphocytes as well as B lymphocytes, macrophages and other immune cells. Some patients with MS are treated with alemtuzumab, a monoclonal antibody against CD52+ cells, which belongs to the disease-modifying therapies (DMTs). The main effect of alemtuzumab is related to changes in immune recruitment. Alemtuzumab therapy can induce secondary autoimmunity against the background of immune rebalancing. The thyroid gland is generally involved in the autoimmune process. Graves' disease (GD) develops most often, followed by autoimmune thyroiditis.We present a clinical case of a patient with GD developed after alemtuzumab therapy for MS. The patient was referred to a radiologist at the Department of Radionuclide Therapy of Endocrinology Research Centre for radioiodine therapy (RAIT) due to relapse of thyrotoxicosis after anti-thyroid drug therapy for GD. The goal of treatment was achieved in 2 months, thyroid hormone therapy was initiated, against the background of this, there was compensation of thyroid function.
Topics: Humans; Alemtuzumab; Iodine Radioisotopes; Neoplasm Recurrence, Local; Graves Disease; Multiple Sclerosis
PubMed: 37448247
DOI: 10.14341/probl13238 -
Blood Advances Jul 2023Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is...
Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 μg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 μg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 μg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.
Topics: Humans; Alemtuzumab; Antibodies, Monoclonal, Humanized; Melphalan; Hematopoietic Stem Cell Transplantation; Tissue Donors; Chemokine CXCL9
PubMed: 37042921
DOI: 10.1182/bloodadvances.2022009478 -
Transplant Infectious Disease : An... Nov 2023Adenovirus (AdV) infection occurs in 0-20% of patients in the first 3-4 months after allogeneic hematopoietic cell transplantation (HCT), being higher in pediatric than... (Review)
Review
Adenovirus (AdV) infection occurs in 0-20% of patients in the first 3-4 months after allogeneic hematopoietic cell transplantation (HCT), being higher in pediatric than in adult patients. About 50% of AdV infections involve the blood, which in turn, correlates with an increased risk developing AdV diseases, end-organ damage, and 6-month overall mortality. The main risk factors for AdV infection are T-cell depletion of the graft by ex vivo selection procedures or in vivo use of alemtuzumab or antithymocyte serum, development of graft versus host disease (GVHD) grade III-IV, donor type (haploidentical or human leucocyte antigen mismatched related donor > cord blood> unrelated matched donor) and severe lymphopenia (<0.2 × 10 /L). The prevention of AdV disease relies on early diagnosis of increasing viral replication in blood or stool and the pre-emptive start of cidofovir as viral load exceeds the threshold of ≥10 copies/mL in blood and/or 10 copies/g stool in the stool. Cidofovir (CDV), a cytosine monophosphate nucleotide analog, is currently the only antiviral recommended for AdV infection despite limited efficacy and moderate risk of nephrotoxicity. Brincidofovir, a lipid derivative of CDV with more favorable pharmacokinetics properties and superior efficacy, is not available and currently is being investigated for other viral infections. The enhancement of virus-specific T-cell immunity in the first few months post-HCT by the administration of donor-derived or third-party-donor-derived virus-specific T-cells represents an innovative and promising modality of intervention and data of efficacy and safety of the ongoing prospective randomized studies are eagerly awaited.
Topics: Adult; Humans; Child; Cidofovir; Prospective Studies; Adenoviridae Infections; Risk Factors; Immunologic Factors; Hematopoietic Stem Cell Transplantation
PubMed: 37846850
DOI: 10.1111/tid.14173 -
Frontiers in Immunology 2023Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T)... (Review)
Review
Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T) therapies as it maximizes engraftment, efficacy and long-term survival of CAR-T. Its main modes of action are the depletion and modulation of endogenous lymphocytes, conditioning of the microenvironment for improved CAR-T expansion and persistence, and reduction of tumor load. However, most LD regimens provide a broad and fairly unspecific suppression of T-cells as well as other hematopoietic cells, which can also lead to severe side effects, particularly infections. We reviewed 1271 published studies (2011-2023) with regard to current LD strategies for approved anti-CD19 CAR-T products for large B cell lymphoma (LBCL). Fludarabine (Flu) and cyclophosphamide (Cy) (alone or in combination) were the most commonly used agents. A large number of different schemes and combinations have been reported. In the respective schemes, doses of Flu and Cy (range 75-120mg/m2 and 750-1.500mg/m2) and wash out times (range 2-5 days) differed substantially. Furthermore, combinations with other agents such as bendamustine (benda), busulfan or alemtuzumab (for allogeneic CAR-T) were described. This diversity creates a challenge but also an opportunity to investigate the impact of LD on cellular kinetics and clinical outcomes of CAR-T. Only 21 studies explicitly investigated in more detail the influence of LD on safety and efficacy. As Flu and Cy can potentially impact both the activity and toxicity of CAR-T, a more detailed analysis of LD outcomes will be needed before we are able to fully assess its impact on different T-cell subsets within the CAR-T product. The T2EVOLVE consortium propagates a strategic investigation of LD protocols for the development of optimized conditioning regimens.
Topics: Receptors, Chimeric Antigen; Adaptor Proteins, Signal Transducing; Alemtuzumab; Antibodies; Cyclophosphamide; Cell- and Tissue-Based Therapy
PubMed: 38187393
DOI: 10.3389/fimmu.2023.1303935 -
Expert Opinion on Drug Safety 2023Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system. Monoclonal antibodies (mAbs) have shown efficacy in reducing MS relapse rates,... (Review)
Review
INTRODUCTION
Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system. Monoclonal antibodies (mAbs) have shown efficacy in reducing MS relapse rates, disease progression, and brain lesion activity.
AREAS COVERED
This article reviews the literature on the use of mAbs for the treatment of MS, including their mechanisms of action, clinical trial data, safety profiles, and long-term outcomes. The review focuses on the three main categories of mAbs used in MS: alemtuzumab, natalizumab, and anti-CD20 drugs. A literature search was conducted using relevant keywords and guidelines and reports from regulatory agencies were reviewed. The search covered studies published from inception to 31 December 202231 December 2022. The article also discusses the potential risks and benefits of these therapies, including their effects on infection rates, malignancies, and vaccination efficacy.
EXPERT OPINION
Monoclonal antibodies have revolutionized the treatment of MS, but safety concerns must be considered, particularly with regards to infection rates, malignancy risk, and vaccination efficacy. Clinicians must weigh the potential benefits and risks of mAbs on an individual patient basis, taking into account factors such as age, disease severity, and comorbidities. Ongoing monitoring and surveillance are essential to ensure the long-term safety and effectiveness of monoclonal antibody therapies in MS.
Topics: Humans; Antibodies, Monoclonal; Multiple Sclerosis; Alemtuzumab; Autoimmune Diseases
PubMed: 37314699
DOI: 10.1080/14740338.2023.2224556 -
Pharmaceuticals (Basel, Switzerland) Nov 2023(1) Background: The purpose of study was to compare the safety profile of glatiramer with natalizumab, alemtuzumab and ocrelizumab in pregnant and lactating women...
(1) Background: The purpose of study was to compare the safety profile of glatiramer with natalizumab, alemtuzumab and ocrelizumab in pregnant and lactating women affected by multiple sclerosis (MS). (2) Methods: Individual case safety reports (ICSRs) were retrieved from the European spontaneous reporting system database (EudraVigilance). The reporting odds ratios (RORs) were computed to compare the reporting probability of events between natalizumab, alemtuzumab and ocrelizumab vs. glatiramer. (3) Results: A total of 1236 ICSRs reporting at least one DMT as a suspected drug were selected. More adverse drug reactions (ADRs) unrelated to pregnancy and breastfeeding ( = 1171; 32.6%) were reported than ADRs specific to pregnancy and breastfeeding ( = 1093; 30.4%). The most frequently reported unrelated ADR was MS relapse. Alemtuzumab and natalizumab seem to have a lower reporting probability of MS relapse compared to glatiramer (ROR 0.17, 95% CI 0.07-0.45 and ROR 0.34, 95% CI 0.20-0.57). Among pregnancy- and breastfeeding-related ADRs, the first most reported event was spontaneous abortion ( = 321; 8.9%). Natalizumab and ocrelizumab were associated with a higher reporting probability of spontaneous abortion compared to glatiramer (ROR 2.22, 95% CI 1.58-3.12; ROR 2.18, 95% CI 1.34-3.54, respectively), while alemtuzumab had a lower reporting frequency (ROR 0.32, 95% CI 0.17-0.60). (4) Conclusions: This study did not suggest any strong or new insights for DMTs in this special subpopulation. However, further studies need to be performed.
PubMed: 38004432
DOI: 10.3390/ph16111566 -
Clinical and Experimental Immunology Jun 2024B and T cells collaborate to drive autoimmune disease (AID). Historically, B- and T-cell (B-T cell) co-interaction was targeted through different pathways such as... (Review)
Review
B and T cells collaborate to drive autoimmune disease (AID). Historically, B- and T-cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B-cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab, or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells, and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T-cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T-cell therapy and T-cell engagers (TCE) that recruit T cells to induce B-cell cytotoxicity have delivered promising results for anti-CD19 CAR T-cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab, or epcoritamab. Limited evidence suggests that anti-CD19 CAR T-cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T-cell collaboration toward overcoming rituximab-resistant AID.
Topics: Humans; Autoimmune Diseases; B-Lymphocytes; T-Lymphocytes; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Rituximab; Cell Communication; Animals
PubMed: 38642912
DOI: 10.1093/cei/uxae031 -
International Immunopharmacology Jul 2023Progressive multiple sclerosis (PMS) is a debilitating condition characterized by progressively worsening symptoms. Monoclonal antibodies are novel therapies for MS, but... (Review)
Review
BACKGROUND
Progressive multiple sclerosis (PMS) is a debilitating condition characterized by progressively worsening symptoms. Monoclonal antibodies are novel therapies for MS, but their safety and efficacy in the progressive form have not been comprehensively studied. In this systematic review, we aimed to evaluate the available evidence regarding monoclonal antibody treatment for PMS.
METHODS
After registration of the study protocol in PROSPERO, we systematically searched three major databases for clinical trials involving monoclonal antibodies administration for PMS treatment. All the retrieved results were imported into the EndNote reference manager. After removing the duplicates, two independent researchers did the study selection and data extraction. The risk of bias was assessed using the Joanna Briggs Institute (JBI) checklist.
RESULTS
Of the 1846 studies in the preliminary search, 13 clinical trials investigating monoclonal antibodies (Ocrelizumab, Natalizumab, Rituximab, and Alemtuzumab) in PMS patients were included. Ocrelizumab was significantly effective in reducing clinical disease progression measures in primary PMS patients. The results for Rituximab were not completely reassuring and only showed significant changes for some endpoints on MRI and clinical measures. Natalizumab decreased the relapse rate and improved MRI features for secondary PMS patients, but not clinical endpoints. The studies on Alemtuzumab treatment revealed conflicting outcomes, with improvements observed in MRI endpoints but clinical worsening in patients. Additionally, among the studied adverse events, upper respiratory infections, urinary tract infections, and nasopharyngitis were frequently reported.
CONCLUSION
Based on our findings, Ocrelizumab is the most efficient monoclonal antibody for primary PMS, although it is associated with a higher risk of infection. While other monoclonal antibodies did not show significant promise in treating PMS, more research is necessary.
Topics: Humans; Antibodies, Monoclonal; Rituximab; Natalizumab; Alemtuzumab; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
PubMed: 37209514
DOI: 10.1016/j.intimp.2023.110266 -
Neurology Feb 2024It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common...
BACKGROUND AND OBJECTIVES
It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common adverse events occurring over the short-term can be captured, and the quality of reporting has been variable. We examined the relationship between the DMDs for MS and potential adverse events in a multiregion population-based study.
METHODS
We identified people with MS using linked administrative health data from 4 Canadian provinces. MS cases were followed from the most recent of first MS or related demyelinating disease event on January 1, 1996, until the earliest of emigration, death, or December 31, 2017. DMD exposure primarily comprised β-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. We examined associations between DMD exposure and infection-related hospitalizations and physician visits using recurrent events proportional means models and between DMD exposure and 15 broad categories of incident adverse events using stratified multivariate Cox proportional hazard models.
RESULTS
We identified 35,894 people with MS. While virtually all DMDs were associated with a 42%-61% lower risk of infection-related hospitalizations, there was a modest increase in infection-related physician visits by 10%-33% for select DMDs. For incident adverse events, most elevated risks involved a second-generation DMD, with alemtuzumab's hazard of thyroid disorders being 19.42 (95% CI 9.29-36.51), hypertension 4.96 (95% CI 1.78-13.84), and cardiovascular disease 3.72 (95% CI 2.12-6.53). Natalizumab's highest risk was for cardiovascular disease (adjusted hazard ratio [aHR] 1.61; 95% CI 1.24-2.10). For the oral DMDs, fingolimod was associated with higher hazards of cerebrovascular (aHR 2.04; 95% CI 1.27-3.30) and ischemic heart diseases (aHR 1.64; 95% CI 1.10-2.44) and hypertension (aHR 1.73; 95% CI 1.30-2.31); teriflunomide with higher hazards of thyroid disorders (aHR 2.30; 95% CI 1.11-4.74), chronic liver disease (aHR 1.94; 95% CI 1.19-3.18), hypertension (aHR 1.76; 95% CI 1.32-2.37), and hyperlipidemia (aHR 1.61; 95% CI 1.07-2.44); and from complementary analyses (in 1 province), dimethyl fumarate with acute liver injury (aHR 6.55; 95% CI 1.96-21.87).
DISCUSSION
Our study provides an extensive safety profile of several different DMDs used to treat MS in the real-world setting. Our findings not only complement those observed in short-term clinical trials but also provide new insights that help inform the risk-benefit profile of the DMDs used to treat MS in clinical practice. The results of this study highlight the continued need for long-term, independent safety studies of the DMDs used to treat MS.
CLASSIFICATION OF EVIDENCE
This study provides Class III evidence that for patients with MS, while DMD exposure reduces the risk of infection-related hospitalizations, there are increased risks of infection-related physician visits and incident adverse events for select DMDs.
Topics: Humans; Multiple Sclerosis; Natalizumab; Alemtuzumab; Canada; Cardiovascular Diseases; Dimethyl Fumarate; Fingolimod Hydrochloride; Hypertension
PubMed: 38181306
DOI: 10.1212/WNL.0000000000208006