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Cladribine is a purine nucleoside analog initially developed in the 1970s as a treatment for various blood cancers. Due to the molecule’s ability to preferentially reduce T and B lymphocytes, it has been developed into an oral formulation for the treatment of multiple sclerosis (MS). The unique proposed mechanism of action of cladribine allows for the therapy to be delivered orally over two treatment-week cycles per year, one cycle at the beginning of the first month and one cycle at the beginning of the second month of years 1 and 2, with the potential for no further cladribine treatment required in years 3 and 4. This review summarizes the clinical development program for cladribine tablets in patients with MS, including the efficacy endpoints and results from the 2-year phase III CLARITY study in patients with relapsing–remitting MS (RRMS), the 2-year CLARITY EXTENSION study, and the phase III ORACLE-MS study in patients with a first clinical demyelinating event at risk for developing MS. Efficacy results from the phase II ONWARD study, in which cladribine tablets were administered as an add-on to interferon-β therapy in patients with RRMS, are also summarized. A review of all safety data, including lymphopenia, infections, and malignancies, is provided based on data from all trials in patients with MS, including the initial parenteral formulation studies. Based on these data, cladribine tablets administered at 3.5 mg/kg over 2 years have been approved across the globe for various forms of relapsing MS. The development of cladribine tablets for the treatment of multiple sclerosis: a comprehensive review (MP4 279143 kb) Enhanced Digital Features To view enhanced digital features for this article, go to 10.1007/s40265-020-01422-9

Background Treatment-emergent adverse events (TEAEs) that occur close to treatment initiation may negatively affect overall tolerability and adherence. It is important to develop a clear understanding of potential early TEAEs after initiating treatment with cladribine tablets. Objective To identify TEAEs that begin early in the course of treatment in patients enrolled in CLARITY and ORACLE-MS studies. Methods This post hoc analysis of CLARITY and ORACLE-MS safety populations assessed the incidence of TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation in patients receiving cladribine tablets or placebo within 2, 6, and 12 weeks after treatment initiation. Results By Week 12, 61.3% of patients treated with cladribine tablets 3.5 mg/kg and 55.2% treated with placebo experienced a TEAE. More patients receiving cladribine tablets versus placebo experienced a drug-related TEAE by Week 12 (34.7% vs. 23.2%). The most common TEAEs reported with cladribine tablets were: headache (7.2%), lymphopenia (6.8%), and nausea (6.0%). Patients receiving cladribine tablets and placebo reported similar proportions of serious TEAEs (2.2% vs. 1.7%) and TEAEs leading to treatment discontinuation (1.6% vs. 1.4%). Conclusion Cladribine tablets were well tolerated during the first 12 weeks as evidenced by a low incidence of TEAEs leading to treatment discontinuation.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Studies in animal models of MS have shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by T cells is necessary for development of autoimmune CNS inflammation. This suggests that GM-CSF may have a pathogenic role in MS as well, and a clinical trial testing its blockade is ongoing. However, there have been few reports on GM-CSF production by T cells in MS. The objective of this study was to characterize GM-CSF production by T cells of MS patients, and to determine the effect of interferon-beta (IFN-β) therapy on its production. GM-CSF production by peripheral blood (PB) T cells and the effects of IFN-β were characterized in samples of untreated and IFN-β-treated MS patients vs. healthy subjects. GM-CSF production by T cells in MS brain lesions was analyzed by immunofluorescence. Untreated MS patients had significantly greater numbers of GM-CSF+ CD4+ and CD8+ T cells in PB compared to healthy controls and IFN-β-treated MS patients. IFN-β significantly suppressed GM-CSF production by T cells in vitro. A number of CD4+ and CD8+ T cells in MS brain lesions expressed GM-CSF. Elevated GM-CSF production by PB T cells in MS is indicative of aberrant hyperactivation of the immune system. Given its essential role in animal models, abundant GM-CSF production at the sites of CNS inflammation suggests that GM-CSF contributes to MS pathogenesis. Our findings also reveal a potential mechanism of IFN-β therapy, namely suppression of GM-CSF production.

The objective of the Therapy Optimization in MS (TOP MS) Study was to prospectively assess the relationship between MS disease-modifying therapy (DMT) adherence and MS relapse risk over 2 years.Potential participants were recruited for TOP MS by specialty pharmacies who dispensed glatiramer acetate and beta interferons for MS nationwide. Signed IRB-approved informed consents were returned to the pharmacies. TOP MS used electronic data capture with monthly patient entries. Adherence, measured by medication possession ratio (MPR), was derived from pharmacy shipment records. Logistic regression examined the association between protocol-defined relapses and DMT MPR (0.5;0.5-0.9;0.9).TOP MS enrolled 3151 persons with MS, and 2410 completed the full 2 years. Across all therapies, the mean MPR for the 2-year completer cohort of 2049 who maintained the same DMT was 0.9+0.2 (range: 0.1-1.0), with 63.8% reaching a 2-year MPR0.9. Evaluated by categories of MPR, the proportion of participants remaining relapse-free for 24 months increased with increasing MPR, and the proportion with1 relapses declined with increasing levels of MPR (p0.0008). Regression analysis revealed the odds of relapse for a patient in the MPR0.9 MPR group was 64% that of a patient in the MPR0.5 category (p=0.02). Use of1 DMT prior to the current one was an independent predictor of relapse.The study provides class III evidence that improvement in adherence to DMT for MS is associated with improved clinical outcomes as measured by relapse reduction.

Zinc overload is an unusual cause of copper-deficiency myeloneuropathy, in which affected patients have low serum copper and ceruloplasmin levels and high serum zinc levels. This Case Study describes a patient whose copper-deficiency myeloneuropathy was secondary to long-term use of a denture cream that contained high levels of zinc. Background A 47-year-old woman with an otherwise unremarkable medical history was referred to the multiple sclerosis clinic by her primary neurologist for evaluation of a 2–3 year history of progressive knee and back pain, weakness, paresthesias, sensory loss, ataxia, and falls. During the same period, she had received blood transfusions for unexplained anemia and leukopenia. She had been wearing dentures for many years. Investigations Physical examination, neurological examinations (assessments of reflexes, gait, proprioception, and sensitivity to temperature, pinprick and vibration), neurophysiological studies (visual and brainstem somatosensory evoked potentials, nerve conduction studies and electromyography), T2-weighted MRI of the brain and spine, cerebrospinal fluid analysis and serum evaluations. Diagnosis Myeloneuropathy and anemia due to copper deficiency, secondary to zinc overload associated with long-term use of denture cream with a high zinc content. Management Change to a low-zinc denture cream and oral copper replacement.

1Comprehensive Multiple Sclerosis Center, Thomas Jefferson University Hospital, Philadelphia, PA, USA; 2Hannover Medical School, Hannover, Germany; 3Austin Health, Heidelberg, VIC, Australia; 4Caritas Krankenhaus Bad Mergentheim, Bad Mergentheim, Germany; 5Genzyme, a Sanofi company, Cambridge, MA, USA; 6Genzyme, a Sanofi company, Chilly-Mazarin, France; 7Sanofi, Chilly-Mazarin, France; 8University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada

This case series reviews the clinical, radiographic and laboratory findings of five patients with progressive idiopathic myelopathy with evidence of cord necrosis who presented in our institution over a 5 year period ending in May 2005. Patients fulfilling the following criteria were included: (1) presentation with myelopathy without overt visual involvement at initial presentation; (2) demonstration with magnetic resonance imaging (MRI) of contiguously abnormal signal in the spinal cord spanning at least three vertebral segments without evidence of arteriovenous malformation or significant disk disease; (3) absence of systemic disease or neoplasm. All patients were women, identified themselves as African American and were older than 35 years. Pain was reported at initial presentation in four cases. The distinctive feature was a relapsing course with intervening variable improvement of function and progression to quadriplegia in less than 4 years. An increased IgG index and/or oligoclonal banding was detected in two patients. The leukocyte count in the cerebrospinal fluid (CSF) was elevated in all cases but in only one specimen did the count exceed 50 cells. None of the patients initially had clinical signs of an optic neuropathy but unilaterally prolonged visual evoked potentials were present in one individual who went on to developed optic neuritis 19 months after the first clinical presentation. Another patient developed optic neuritis 45 months after disease onset. Immunomodulatory and plasma exchange therapy were of some benefit at least early in the course but the disease progressed despite these interventions. Neuromyelitis optica (NMO)-IgG antibody, a serum or CSF marker described in individuals with classic NMO and optico-spinal multiple sclerosis (MS), was present in all cases. On the basis of shared clinical and imaging features in the cord, progressive necrotizing myelopathy observed in this case series exhibits key features of a limited form of NMO (Devic's disease) and opticospinal MS. The presence of NMO-IgG antibody marker suggests that progressive necrotizing myelopathy is part of a disease spectrum of which traditional NMO is a select presentation.

Conventional magnetic resonance imaging (MRI) has routinely been used to improve the accuracy of multiple sclerosis (MS) diagnosis and monitoring, detect the effects of disease-modifying therapy, and refine the utility of clinical assessments. However, conventional MRI measures, such as the use of lesion volume and count of gadolinium-enhancing and T2 lesions, have insufficient sensitivity and specificity to reveal the true degree of pathological changes occurring in MS. Newer metrics of MRI analysis, including T1-weighted hypointense lesions (black holes) and central nervous system (CNS) atrophy measures, are able to capture a more global picture of the range of tissue alterations caused by inflammation, demyelination, axonal loss, and neurodegeneration. There is mounting evidence that these MRI measures correlate well with existing and developing neurological impairment and disability. In so doing, these MRI techniques can help elucidate the mechanisms underlying the pathophysiology and natural history of MS. The current understanding is that T1 black holes and CNS atrophy more accurately reflect the neurodegenerative and destructive components of the MS disease process. Therefore, the short and long-term studies that aim to measure the degree and severity of the neurodegenerative MS disease process should incorporate these MRI metrics as part of their standard routine MRI protocols.

BACKGROUND An objective demonstration of lesions disseminated in time and space remains the core of the last revision of diagnostic criteria for multiple sclerosis (MS), but this update is now empowered by a weighted use of magnetic resonance imaging (MRI), which results in an earlier and more unambiguous diagnosis ("MS," "not MS," or "possible MS"). Nevertheless, the exclusion of other entities still remains an integral element of the diagnostic process. REVIEW SUMMARY Exclusion of genetic disorders can be challenging in some cases with familial recurrence of MS, particularly when the transmission is mimicking a mendelian or a maternal pattern of inheritance. Vice versa, many forms of mendelian leukodystrophies and leukoencephalopathies present with juvenile or adult onset, progressive or relapsing-remitting courses, intrafamilial phenotypic heterogeneity and MRI signs of multifocal white matter (WM) pathology, features potentially leading to a temporary confusion with MS. With the recent availability of disease modifying medications in MS, the development of specific molecular therapies in inherited WM disorders, and the general recognition of the effectiveness of early treatments, the accuracy of initial diagnostic assessment has become critical. CONCLUSION Considering the importance of disease specific treatments, here we review the major characteristics of familial MS and some of the inheritable diseases of the WM. Although no direct genetic link between MS and these WM abnormalities is known, molecular data from the field of rare genetic disorders may also provide some experimental paradigms to a further exploration of MS.

Neurodegeneration is the main pathological correlate of accumulating disability in progressive stages of Multiple Sclerosis (MS), but both histologic and imaging studies detect significant tissue loss even in early disease. These observations raise the question as to whether neurodegeneration in MS is a primary mechanism or whether it develops secondary to inflammation and demyelination. Recent data suggest that the atrophy of brain and cord is directly linked to inflammation and may partly be independent of demyelination. Released products of both residential and infiltrating immune cells can induce ultrastructural changes and cell-death by multiple mechanism. We propose that the inflammation-induced tissue response is controlled by genetic variations and to some extent involves a mitochondrion-driven mechanism in MS, similar to that described in the final pathway of other neurodegenerative disorders. Current therapeutic strategies primarily target the immune system which results in a successful down-regulation of plaque formation and of relapse rate. However, measures of clinical disability best correlate with the degree of neurodegeneration rather than with the volume of plaques, and these immune-modulating regimens may only incompletely affect the accumulating tissue loss. Considering the need for additional therapeutic strategies, we emphasize the degenerative components, and review a mitochondrial mechanism of tissue loss potentially involved in the process of MS.

Since the first description of multiple sclerosis (MS) as an inheritable disease by Eichhorst [1] accumulating epidemiological observations support a genetic hypothesis. Population, family and twin studies have revealed that Mendelian transmission of a single susceptibility gene would not be compatible with the observed patterns of inheritance. Like most other common diseases, MS is a complex trait, defined by several genes, each probably exerting a relatively small effect. Complex interactions among susceptibility genes and the environment are believed to contribute to a predisposition to dysregulation of inflammatory pathways, demyelination and tissue degeneration in the central nervous system (CNS). Natural history and pathological studies, however, define that MS represents a spectrum rather than a single entity of inflammatory demyelination. Despite a growing need for identifying molecular markers of biological subtypes of MS, only limited information is available for genotype-phenotype correlations. Four full genome scans using polymorphic microsatellite markers in nuclear and multiplex MS families indicated several chromosomal regions of susceptibility. With the recently discovered, highly abundant single nucleotide polymorphisms (SNPs) and family-based association methods, the means are now available to confine these relatively large regions of interest to candidate genes and susceptibility alleles. The currently available SNP maps favor indirect association studies based on linkage disequilibrium between marker and disease alleles. Here, we review available genetic data in MS, and introduce an additional strategy which correlate genetic markers with major biological components of the disease such as autoimmunity and neurodegeneration. This approach may yield important insights with utility in clinical practice.

Peroxynitrite has been implicated in the pathogenesis of multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). Previously, we have shown that administration of uric acid (UA), a peroxynitrite scavenger, is therapeutic in EAE. We have also shown that MS patients have lower levels of serum uric acid than healthy individuals or those with other neurological diseases. The aim of this investigation was therefore to raise serum UA levels in MS patients. Oral administration of UA failed to increase low serum UA levels, evidently due to its degradation by gastrointestinal bacteria. However, serum UA could be raised and maintained at elevated levels for a year and more without reported side-effects by oral administration of its precursor inosine. Three of 11 patients given inosine showed some evidence of clinical improvement and there was no sign of disease progression in the remaining patients. Gadolinium-enhanced lesions, observed in two patients before receiving inosine, could not be detected after either 10 or 15 months inosine treatment. These data provide evidence that serum UA levels can be readily manipulated and that the benefit of higher levels to individuals with MS should be studied further in greater number of patients.

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disease that results from an interaction of retroviral infection and immune activation. In this study, five doses (1 mg/kg) of humanized anti-Tac antibody were administered to 9 HAM/TSP patients at weeks 0, 2, 6, 10, and 14. Preliminary immunological studies on HAM/TSP patients treated with humanized anti-Tac indicate that there is a selective down-regulation of activated T cells and a decrease in the HTLV-I viral load in peripheral blood lymphocytes, most likely through the selective removal of HTLV-I-infected, activated CD4+ lymphocytes.

The roles of tumor necrosis factor (TNF alpha) and reactive nitrogen intermediates (RNI) as effectors of macrophage-mediated tumor cell killing were investigated in a variety of tumor cell lines. Three TNF alpha-sensitive tumor targets were also susceptible to resting bone-marrow-derived mononuclear phagocytes (BMMP). This macrophage lytic activity was markedly diminished or even abolished by anti-TNF alpha, indicating that TNF alpha is the major effector of macrophage-mediated killing of these targets. The other 21 tumor cell lines examined were resistant to TNF alpha but, in their large majority, were more or less susceptible to killing by interferon gamma (IFN gamma)- and Corynebacterium parvum (CP)-activated BMMP. Among the various analogues of L-arginine used to assess the role of L-arginine-derived RNI as mediators of macrophage tumoricidal activity, NG-monomethyl-L-arginine (NMMA) was most efficient in suppressing RNI secretion by activated macrophages. In some macrophage tumor-cell combinations, NMMA inhibited both the generation of RNI and the expression of tumoricidal activity in a dose-dependent manner, suggesting a central role for RNI as effectors. In other combinations, NMMA in concentrations that abolished secretion of RNI either affected tumor-cell killing only after its induction by IFN gamma, or not at all. The findings not only support the thesis that macrophages posses various means of coping with tumor cells but also suggest that the mechanism becoming operative is determined predominantly by the pathway of macrophage activation and the properties of the tumor-cell type.

The 77C→ G polymorphism in exon 4 of CD45 or protein tyrosine phosphatase receptor-type C (PTPRC) has been investigated in families with multiple sclerosis (MS) and in several cohorts of sporadic patients and controls, however, with conflicting results. To better understand the role of this functionally important polymorphism in MS, we investigated the transmission of the ‘G’ allele from unaffected parents to their affected children in 176 families by using linkage and association statistics. The ‘G’ allele was transmitted to the affected offspring in five of the seven pedigrees carrying this allele and the TRANSMIT program detected association with a P -0.0342. We conclude that the 77C→ G PTPRC polymorphism is present and preferentially transmitted in a small subgroup (< 5%) of MS families, which may only be detected with complementary methods of analysis.

During generalized immune responses such as the acute phase of graft-vs.-host reaction (GvHR) or many systemic viral infections the macrophage-monocyte system of mice is activated as demonstrated by their increased bactericidal capacity against Listeria monocytogenes. To study the effect of interferon (IFN)-gamma in maintainance of macrophage activity, lymphocytic choriomeningitis virus (LCMV) primed C57BL/6 mice or (C57BL/10 x B10.BR) F1 mice undergoing a GvHR were treated with polyclonal specific sheep anti-IFN-gamma antiserum. In both cases injection of anti-IFN-gamma resulted in inhibition of the stimulatory effects on macrophages as detected by reduced bactericidal activity when compared to mice treated with normal serum. Treatment with a polyclonal sheep anti-IFN-alpha,beta antiserum on the other hand did not interfere with the activation status of the macrophages. The findings suggest that IFN-gamma is produced both early in a GvHR and during the acute phase of an systemic infection with LCMV, and that it is involved in in vivo modulation of the increased activity of mononuclear phagocytes in immunologically stimulated mice.