The association between lymphopenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple ...sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28 ⁻CD57 ⁺), highly proliferative (Ki67 ⁺), oligoclonal, memory-like CD4 and CD8 T cells (CCR7 ⁻CD45RA ⁻ or CCR7 ⁻CD45RA ⁺) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopenic than their nonautoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopenia-associated autoimmunity in humans.
Hyperpolarized 13C Magnetic Resonance Imaging (13C-MRI) provides a highly sensitive tool to probe tissue metabolism in vivo and has recently been translated into clinical studies. We report the ...cerebral metabolism of intravenously injected hyperpolarized 1–13Cpyruvate in the brain of healthy human volunteers for the first time. Dynamic acquisition of 13C images demonstrated 13C-labeling of both lactate and bicarbonate, catalyzed by cytosolic lactate dehydrogenase and mitochondrial pyruvate dehydrogenase respectively. This demonstrates that both enzymes can be probed in vivo in the presence of an intact blood-brain barrier: the measured apparent exchange rate constant (kPL) for exchange of the hyperpolarized 13C label between 1–13Cpyruvate and the endogenous lactate pool was 0.012 ± 0.006 s−1 and the apparent rate constant (kPB) for the irreversible flux of 1–13Cpyruvate to 13Cbicarbonate was 0.002 ± 0.002 s−1. Imaging also revealed that 1–13Cpyruvate, 1–13Clactate and 13Cbicarbonate were significantly higher in gray matter compared to white matter. Imaging normal brain metabolism with hyperpolarized 1–13Cpyruvate and subsequent quantification, have important implications for interpreting pathological cerebral metabolism in future studies.
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OBJECTIVE:To evaluate 5-year efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting MS (RRMS) (CARE-MS I; NCT00530348).
METHODS:Alemtuzumab-treated patients ...received treatment courses at baseline and 12 months later; after the core study, they could enter an extension (NCT00930553) with as-needed alemtuzumab retreatment for relapse or MRI activity. Assessments included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale EDSS score increase ≥1.5 if baseline EDSS = 0), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease baseline score ≥2.0), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs).
RESULTS:Most alemtuzumab-treated patients (95.1%) completing CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment. ARR remained low in years 3, 4, and 5 (0.19, 0.14, and 0.15). Over years 0–5, 79.7% were free of 6-month CDW; 33.4% achieved 6-month CDI. Most patients (61.7%, 60.2%, and 62.4%) had NEDA in years 3, 4, and 5. Median yearly BVL improved over years 2–4, remaining low in year 5 (years 1–5−0.59%, −0.25%, −0.19%, −0.15%, and −0.20%). Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study. Thyroid disorder incidences peaked at year 3 and subsequently declined.
CONCLUSIONS:Based on these data, alemtuzumab provides durable efficacy through 5 years in the absence of continuous treatment, with most patients not receiving additional courses.
CLINICALTRIALS.GOV IDENTIFIER:NCT00530348; NCT00930553.
CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that alemtuzumab durably improves efficacy outcomes and slows BVL in patients with RRMS.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Newer therapies for multiple sclerosis Coles, Alasdair
Annals of the Indian Academy of Neurology,
09/2015, Letnik:
18, Številka:
Suppl 1
Journal Article
Recenzirano
Odprti dostop
The newer immunotherapies for multiple sclerosis (fingolimod, natalizumab, dimethyl fumarate, teriflunomide, alemtuzumab) offer advantages of efficacy or tolerability over the injectable therapies of ...the 1990s. But they also have greater risks. As further treatments emerge (daclizumab and ocrelizumab are likely to be licensed in the next two years), the physician needs to be able to place them within a complex landscape of drugs and a specific treatment strategy, which may be an "escalation" or "induction" approach. Whilst on treatment, neurologist and patient need to be vigilant to signs of disease breakthrough or adverse effects.
Psychiatrists need to be vigilant for the newly recognised and treatable disorder of antibody-mediated encephalitis. Psychiatric symptoms are common, and individuals with the disorder often present ...initially to psychiatric services. We describe the clinical features of the disorder and make recommendations for further investigations.
Alemtuzumab is a humanized monoclonal antibody directed against CD52. A single cycle of alemtuzumab, administered over 5 days, depletes lymphocytes. Reconstitution causes prolonged alterations in the ...lymphocyte repertoire, with relatively increased regulatory T-cell numbers and reduced naïve T cells. It is currently approved for the treatment of B-cell chronic lymphocytic leukemia and is being considered for licensing for multiple sclerosis (MS).When first used, alemtuzumab successfully reduced relapses and new lesion formation based on magnetic resonance imaging in people with progressive MS, but this cohort continued to accumulate disability, associated with progressive cerebral atrophy, presumably due to axonal degeneration. From this experience, we advocated that immunotherapies should be given early in the course of the disease. Since then, one phase II and two phase III trials have shown that alemtuzumab reduces the relapse rate, compared with the active comparator interferon beta-1a (IFNβ-1a), in treatment-naïve and treatment-experienced MS up to 10 years from disease onset. Furthermore, in two of these trials, alemtuzumab reduced the risk of accumulating disability compared with IFNβ-1a; indeed alemtuzumab treatment led to an improvement in disability and reduction in cerebral atrophy. Safety issues are infusion-associated reactions, mainly controlled by methyl-prednisolone, antihistamines, and antipyretics; mild to moderate infections; and autoimmunity. After 5 years, 30 to 40% of alemtuzumab patients have developed autoimmunity, largely against the thyroid gland, but rarely (2%) against platelets in immune thrombocytopenia, and in a few cases, Goodpasture's renal syndrome.Alemtuzumab is an effective therapy for early relapsing-remitting multiple sclerosis, offering disability improvement at least to 5 years after treatment. Its use requires careful monitoring so that potentially serious side effects can be treated early and effectively.
The Cambridge Centre for Myelin Repair One (CCMR-One) trial showed that 6 months of bexarotene reduces visual evoked potential (VEP) latency in people with relapsing-remitting multiple sclerosis ...(MS). In a single-centre follow-up study of these participants, we re-examined full-field VEP and clinical assessments. Twenty participants (12 bexarotene and 8 placebo) were seen on average 27 months after their trial involvement. In an analysis of all eyes with recordable signal (24 bexarotene and 14 placebo), the adjusted bexarotene-placebo treatment difference in P100 latency was -7.79 (95% confidence interval (CI) = -14.76, -0.82) ms,
= 0.044. We conclude that there were durable improvements in VEP latency, suggesting long-term benefits from exposure to a remyelinating drug.
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