Treatment of early relapsing–remitting multiple sclerosis with the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath registered trade mark) significantly reduced the risk of ...relapse and accumulation of disability compared with interferon β-1a in a phase 2 trial Coles et al., (Alemtuzumab vs. interferon β-1a in early multiple sclerosis. N Engl J Med 2008; 359: 1786–801). Patients treated with alemtuzumab experienced an improvement in disability at 6 months that was sustained for at least 3 years. In contrast, those treated with interferon β-1a steadily accumulated disability. Here, by post hoc subgroup analyses of the CAMMS223 trial, we show that among participants with no clinical disease activity immediately before treatment, or any clinical or radiological disease activity on-trial, disability improved after alemtuzumab but not following interferon β-1a. This suggests that disability improvement after alemtuzumab is not solely attributable to its anti-inflammatory effect. So we hypothesized that lymphocytes, reconstituting after alemtuzumab, permit or promote brain repair. Here we show that after alemtuzumab, and only when specifically stimulated with myelin basic protein, peripheral blood mononuclear cell cultures produced increased concentrations of brain-derived neurotrophic factor, platelet-derived growth factor and ciliary neurotrophic factor. Analysis by reverse transcriptase polymerase chain reaction of cell separations showed that the increased production of ciliary neurotrophic factor and brain-derived neurotrophic factor after alemtuzumab is attributable to increased production by T cells. Media from these post-alemtuzumab peripheral blood mononuclear cell cultures promoted survival of rat neurones and increased axonal length in vitro, effects that were partially reversed by neutralizing antibodies against brain-derived nerve growth factor and ciliary neurotrophic factor. This conditioned media also enhanced oligodendrocyte precursor cell survival, maturation and myelination. Taken together, the clinical analyses and laboratory findings support the interpretation that improvement in disability after alemtuzumab may result, in part, from neuroprotection associated with increased lymphocytic delivery of neurotrophins to the central nervous system.
Background:
In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved ...outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing–remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline.
Methods:
Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN–alemtuzumab), followed by additional, as-needed, alemtuzumab.
Results:
Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN–alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN–alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups.
Conclusion:
This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups.
ClinicalTrials.gov identifiers:
NCT00530348; NCT00548405; NCT00930553
Background:
Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population.
Objective:
Describe ...instances of autoimmune nephropathy in alemtuzumab-treated MS patients.
Methods:
Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use.
Results:
As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria.
Conclusion:
Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely.
Increasing evidence implicates B cells in the pathogenesis of multiple sclerosis. Smets et al. report that the CD40 multiple sclerosis risk allele lowers CD40 expression, whereas the CD86 risk allele ...increases CD86 expression. B cells may have an important antigen presentation and immunoregulatory role in multiple sclerosis.
Abstract
The increasing evidence supporting a role for B cells in the pathogenesis of multiple sclerosis prompted us to investigate the influence of known susceptibility variants on the surface expression of co-stimulatory molecules in these cells. Using flow cytometry we measured surface expression of CD40 and CD86 in B cells from 68 patients and 162 healthy controls that were genotyped for the multiple sclerosis associated single nucleotide polymorphisms (SNPs) rs4810485, which maps within the CD40 gene, and rs9282641, which maps within the CD86 gene. We found that carrying the risk allele rs4810485*T lowered the cell-surface expression of CD40 in all tested B cell subtypes (in total B cells P ≤ 5.10 × 10−5 in patients and ≤4.09 × 10−6 in controls), while carrying the risk allele rs9282641*G increased the expression of CD86, with this effect primarily seen in the naïve B cell subset (P = 0.048 in patients and 5.38 × 10−5 in controls). In concordance with these results, analysis of RNA expression demonstrated that the risk allele rs4810485*T resulted in lower total CD40 expression (P = 0.057) but with an increased proportion of alternative splice-forms leading to decoy receptors (P = 4.00 × 10−7). Finally, we also observed that the risk allele rs4810485*T was associated with decreased levels of interleukin-10 (P = 0.020), which is considered to have an immunoregulatory function downstream of CD40. Given the importance of these co-stimulatory molecules in determining the immune reaction that appears in response to antigen our data suggest that B cells might have an important antigen presentation and immunoregulatory role in the pathogenesis of multiple sclerosis.
Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this ...difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6-12 mo), and long-term (6-13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.
A case of anaphylaxis to alemtuzumab Nye, Charles J. S.; Wagner, Annette; Kousin-Ezewu, Onajite ...
Journal of neurology,
1/3, Letnik:
266, Številka:
3
Journal Article
IntroductionObservational studies indicate a potentially causal role for interleukin 6 (IL-6), a proinflammatory cytokine, in pathogenesis of depression, but interventional studies based on patients ...with depression have not been conducted. Tocilizumab, anti-inflammatory drug, is a humanised monoclonal antibody that inhibits IL-6 signalling and is licensed in the UK for treatment of rheumatoid arthritis. The main objectives of this study are to test whether IL-6 contributes to the pathogenesis of depression and to examine potential mechanisms by which IL-6 affects mood and cognition. A secondary objective is to compare depressed participants with and without evidence of low-grade systemic inflammation.Methods and analysisThis is a proof-of-concept, randomised, parallel-group, double-blind, placebo-controlled clinical trial. Approximately 50 participants with International Classification of Diseases 10th revision (ICD-10) diagnosis of depression who have evidence of low-grade inflammation, defined as serum high-sensitivity C reactive protein (hs-CRP) level ≥3 mg/L, will receive either a single intravenous infusion of tocilizumab or normal saline. Blood samples, behavioural and cognitive measures will be collected at baseline and after infusion around day 7, 14 and 28. The primary outcome is somatic symptoms score around day 14 postinfusion. In addition, approximately, 50 depressed participants without low-grade inflammation (serum hs-CRP level <3 mg/L) will complete the same baseline assessments as the randomised cohort.Ethics and disseminationThe study has been approved by the South Central—Oxford B Research Ethics Committee (REC) (Reference: 18/SC/0118). Study findings will be published in peer-review journals. Findings will be also disseminated by conference/departmental presentations and by social and traditional media.Trial registration number ISRCTN16942542; Pre-results.
We present a case of cerebellar dysfunction due to severe hypothyroidism induced by pembrolizumab, a member of the 'immune checkpoint inhibitor' class of cancer immunotherapies. Thyroxine replacement ...completely resolved his symptoms and signs. We also discuss the neurological immune-related complications of checkpoint inhibitors.
Multiple sclerosis is the most common, non-traumatic, disabling neurological disease of young adults, affecting an estimated two million people worldwide. At onset multiple sclerosis can be ...categorised clinically into relapsing remitting MS (RRMS — 85–90% of patients) or primary progressive MS (PPMS). Relapses typically present sub-acutely over hours to days with neurological symptoms persisting for days to weeks before they gradually dissipate. At first full recovery is the norm, later patients accumulate deficits and ultimately most convert to a secondary progressive phase (SPMS), characterised by deficits that increase in the absence of further relapses. The clinical picture reflects the complex interplay of focal inflammation, demyelination and axonal degeneration occurring within the central nervous system.
Since the introduction of a genuine disease-modifying drug, interferon-beta1b in 1993, there has been a growing interest from academia and pharmaceutical companies alike in multiple sclerosis therapy. In part this effort has focused on investigating the “window of therapeutic opportunity” within the natural history of the disease: it is becoming increasingly clear that immunotherapies are not useful in the secondary phase of the disease but may offer long-term benefit if given early in the relapsing–remitting phase. In part, attention is being paid to the details of dosing and administration of the various licensed therapies, but there is also a significant research effort to explore new ways to treat the disease. In this review, we first sketch the landscape of novel therapies in multiple sclerosis and then discuss in detail approaches which are likely to emerge over the next few years.
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