Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the ...perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore, it was interestingly to find that current MS-treatments, believed to act via T cell inhibition, including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19+, CD27+ memory B cells. This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity. Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS. This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.
•Memory B cells activity is consistent with the etiology, pathology and therapy of MS, thought to be T cell-mediated.•Deletion of memory B cells occurs with all effective MS treatments and is more marked with high-efficacy treatments.•Drugs that worsen MS, can also increase memory B cell production.
New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the ...highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein–Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention.
Clinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients.B cell-tropic viruses may trigger aberrant immune responses in MS in genetically susceptible individuals owing, in part, to a failure in viral surveillance and clearance.The most compelling data supporting an etiologic role for viral involvement in MS have emerged for Epstein–Barr virus (EBV).Targeting mechanisms by which EBV is thought to participate in MS pathogenesis provides an opportunity for new drug development in MS.
In two trials involving patients with relapsing multiple sclerosis, the anti-CD20+ monoclonal antibody ocrelizumab was associated with lower annualized relapse rates, lower risk of disability ...progression, and better MRI features than interferon beta-1a.
Despite the availability of several disease-modifying treatments for relapsing forms of multiple sclerosis, patients often continue to have clinical and subclinical disease activity, and neurologic disability continues to accrue. Thus, there is a need for more effective treatments with acceptable safety profiles.
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B cells are thought to influence the underlying pathogenesis of multiple sclerosis by means of antigen presentation,
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autoantibody production,
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cytokine regulation,
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and the formation of ectopic lymphoid aggregates in the meninges, which possibly contribute to cortical demyelination and neurodegeneration.
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Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20, a cell-surface antigen that is expressed . . .
In 215 patients with a median age of 16 years, fingolimod was superior to interferon beta-1a in reducing relapses of multiple sclerosis and the accumulation of new lesions on MRI over a 2-year ...period. Seizures occurred in 5.6% of patients in the fingolimod group.
Background:
No evidence of disease activity (NEDA-3) is a patient-centric outcome increasingly used as the goal of multiple sclerosis treatment.
Objective:
Determine treatment durability of ...cladribine tablets beyond 2 years considering the variable bridging interval of 0.1–116.0 weeks between CLARITY and CLARITY Extension.
Methods:
Between CLARITY and CLARITY Extension, patients transitioned from cladribine tablets 3.5 mg/kg to placebo (CP3.5 group, n = 98) or continued further treatment with cladribine tablets 3.5 mg/kg (CC7.0 group, n = 186). Treatment assignment was randomized and blinded in both CLARITY and CLARITY Extension.
Results:
The 2-year NEDA-3 in CLARITY Extension (encompassing both years of CLARITY Extension) was 29.6% in the CP3.5 group and 32.8% in the CC7.0 group. There was no evidence that treatment effect differed with varying bridging intervals. For patients in the CP3.5 group with a bridging interval of ⩽48 weeks, 1 year NEDA-3 (the first year of CLARITY Extension) was 44.4% (28/63) compared with 31.4% (11/35) in patients with a bridging interval of >48 weeks.
Conclusion:
Treatment with cladribine tablets in CLARITY, followed by either placebo or cladribine tablets in CLARITY Extension, produced sustained benefits for NEDA-3 and its constituent elements for a follow up period up to 6 years from CLARITY baseline.
ObjectivesThe aims of this manuscript were to review the evidence for the efficacy and safety of cladribine in multiple sclerosis (MS) and to review the molecular and cellular mechanisms by which ...cladribine acts as a disease-modifying therapy in MS.MethodsThis is a narrative review of the available clinical and preclinical data on the use of cladribine in MS.ResultsClinical trial data argue strongly that cladribine is a safe and effective therapy for relapsing MS and that it may also be beneficial in progressive MS. The pharmacology of cladribine explains how it is selectively toxic towards lymphocytes. Immunophenotyping studies show that cladribine depletes lymphocyte populations in vivo with a predilection for B cells. In vitro studies demonstrate that cladribine also exerts immunomodulatory influences over innate and adaptive immunity.ConclusionsCladribine is a safe and effective form of induction therapy for relapsing MS. Its mechanism of benefit is not fully understood but the most striking action is selective, long-lasting, depletion of B lymphocytes with a particular predilection for memory B cells. The in vivo relevance of its other immunomodulatory actions is unknown. The hypothesis that cladribine’s action of benefit is to deplete memory B cells is important: if correct, it implies that selective targeting of this cell population and sparing of other lymphocytes could modify disease activity without predisposing to immunosuppression-related complications.
Objective:
To evaluate the association between diagnosis of Parkinson disease (PD) and risk factors or early symptoms amenable to population‐based screening.
Methods:
A systematic review and ...meta‐analysis of risk factors for PD.
Results:
The strongest associations with later diagnosis of PD were found for having a first‐degree or any relative with PD (odds ratio OR, 3.23; 95% confidence interval CI, 2.65–3.93 and OR, 4.45; 95% CI, 3.39–5.83) or any relative with tremor (OR, 2.74; 95% CI, 2.10–3.57), constipation (relative risk RR, 2.34; 95% CI, 1.55–3.53), or lack of smoking history (current vs never: RR, 0.44; 95% CI, 0.39–0.50), each at least doubling the risk of PD. Further positive significant associations were found for history of anxiety or depression, pesticide exposure, head injury, rural living, beta‐blockers, farming occupation, and well‐water drinking, and negative significant associations were found for coffee drinking, hypertension, nonsteroidal anti‐inflammatory drugs, calcium channel blockers, and alcohol, but not for diabetes mellitus, cancer, oral contraceptive pill use, surgical menopause, hormone replacement therapy, statins, acetaminophen/paracetamol, aspirin, tea drinking, history of general anesthesia, or gastric ulcers. In the systematic review, additional associations included negative associations with raised serum urate, and single studies or studies with conflicting results.
Interpretation:
The strongest risk factors associated with later PD diagnosis are having a family history of PD or tremor, a history of constipation, and lack of smoking history. Further factors also but less strongly contribute to risk of PD diagnosis or, as some premotor symptoms, require further standardized studies to demonstrate the magnitude of risk associated with them. ANN NEUROL 2012
Background:
Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting ...MS (RRMS; CLARITY and CLARITY Extension). This analysis compared the effect of cladribine tablets on the dynamics of immune cell reduction and reconstitution in ORACLE-MS, CLARITY, and CLARITY Extension during the first year of treatment (i.e. the first course of CT1.75) in patients randomized to CT3.5.
Methods:
Lymphocyte subtypes were analyzed using multiparameter flow cytometry. Changes in cell counts and relative proportions of lymphocytes were evaluated at weeks 5, 13, 24, and 48.
Results:
Across studies, consistent and comparable selective kinetics of immune cell populations occurred following the first treatment year with CT. A rapid reduction in CD16+/CD56+ cells (week 5 nadir), a more marked reduction in CD19+ B cells (week 13 nadir), and a less-pronounced effect on CD4+ (week 13 nadir) and CD8+ T cells (week 24 nadir) was shown. There was little effect on neutrophils or monocytes. Lymphocyte recovery began after treatment with CT3.5. Regarding relative proportions of naïve and memory T-cell subtypes in ORACLE-MS, the proportion of naïve-like naturally occurring T-regulatory cells (nTregs) decreased, and the proportion of memory-like nTregs increased, relative to total CD4+ T cells.
Conclusions:
CT3.5 has comparable effects on the immune systems of patients with CIS or RRMS. The pronounced reduction and recovery dynamics of CD19+ B cells and relative changes in the proportion of some immune cell subtypes may underlie the clinical effects of CT3.5.
The Multiple Sclerosis Care Unit Soelberg Sorensen, Per; Giovannoni, Gavin; Montalban, Xavier ...
Multiple Sclerosis Journal,
04/2019, Volume:
25, Issue:
5
Book Review, Journal Article
Peer reviewed
Open access
Treatment of multiple sclerosis (MS) has become increasingly multifaceted and comprises not only a variety of disease-modifying drugs with different mechanism of action but also a wide range of ...symptomatic therapies. Today, it is not possible for the family physician or even many general neurologists to master the current treatment algorithm, and this calls for the establishment of multidisciplinary MS Care Units. The core of the MS Care Unit would, in addition to MS neurologists and nurses, typically comprise neuropsychologists, clinical psychologists, physiotherapists, occupational therapists and secretaries, and will work together with a group of different specialists on formalized diagnostic workup procedures, protocols for initiation and follow-up of disease-modifying therapies. It is obvious that the terms of performance of different MS Care Units will vary across regions and need to be balanced with clinical practice according to local conditions. Although the main objective for establishment of MS Care Units will be to offer the single MS patient seamless and correct management of the disease to increase patient satisfaction and quality of life, it may even be cost-effective for the society by maintaining the working ability and reducing the costs of home help and custodial care by keeping people with MS resourceful.
Cladribine is a purine nucleoside analogue that selectively depletes peripheral lymphocytes without a major impact on cells of the innate immune system. An oral formulation of cladribine has been ...developed to be given as short courses over two annual cycles. Oral cladribine results in the peripheral depletion of lymphocytes that is gradual, occurring over several weeks, and is not associated with a cell lysis syndrome, has a greater impact on B cells than T cells, and is followed by gradual reconstitution of the peripheral lymphocyte counts over several months. Oral cladribine is effective in relapsing forms of multiple sclerosis. As a selective immune reconstitution therapy (SIRT), cladribine acts as a short-term immunosuppressant, relative to other maintenance immunosuppressive therapies that result in long-term immunosuppression. The main safety signal that has emerge relates primarily to herpes zoster infection, which was more common in patients with higher grades of lymphopenia, in particular grade 3 and 4 lymphopenia. Data from the oral cladribine extension trial and safety register, and reanalysis of the pivotal phase III trial has indicated that oral cladribine is unlikely to be associated with an increased short- to intermediate-term risk of malignancy.
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