Richard Nicholas

Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group

The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk.

Anticholinergics for urinary symptoms in multiple sclerosis

BACKGROUNDnMultiple Sclerosis (MS) is the commonest physically disabling chronic neurological disease affecting young people. Urinary symptoms are present in about 68% of people with MS but their basis has a number of potential aetiologies that can change with time.nnnOBJECTIVESnTo assess the absolute and comparative efficacy, tolerability and safety of anticholinergic agents in MS patients.nnnSEARCH STRATEGYnWe searched the Cochrane Multiple Sclerosis Group Specialised Trials Register, the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue1), MEDLINE (January 1966 to January 2008), EMBASE (January 1974 to January 2008), supplemented with search of reference lists, personal communication with authors and relevant drug manufacturers.nnnSELECTION CRITERIAnRandomised trials and cross-over trials (blinded and unblinded) that are either placebo-controlled or comparing two or more treatments.nnnDATA COLLECTION AND ANALYSISnAll four review authors independently assessed eligibility and trial quality, and extracted data. Data were processed as described in the Cochrane Handbook for Systematic Reviews of Interventions.nnnMAIN RESULTSnOur search strategy identified 33 articles of which thirty were excluded. Three single centre trials were included. No details were given regarding randomisation and blinding in the first two trials but side effects were frequent with all treatments.The first (Hebjorn 1977) was a double blind randomised crossover trial. Thirty four persons with MS received three drugs Methantheline Bromide, Flavoxate Chloride and Meladrazine Tartrate each for 14 days, washout periods were not mentioned. Median volume measurements at the first bladder contraction were statistically significant at a 5% level for Methantheline Bromide only compared to no treatment.The second (Gajewski 1986) was a prospective parallel group randomised study. Thirty four persons with MS were treated for 6-8 weeks with Oxybutynin (19 subjects) or Propantheline (15 subjects). For frequency, nocturia, urgency, and urge incontinence differences in symptom grade in favour of Oxybutynin were found. However, only for frequency the difference was statistically significant at 5% level.The third (Fader 2007) was a double blind crossover trial. Sixty four persons with MS received oral Oxybutynin or intravesical Atropine for 14 days. Details of randomisation and blinding were given. There was no significant difference between the two treatments in any efficacy outcome measure. Side effects and QOL scores showed significant differences in favour of atropine.nnnAUTHORS CONCLUSIONSnFrom the available evidence we cannot advocate the use of anticholinergics in MS.

Development of oral immunomodulatory agents in the management of multiple sclerosis.

The emergence of oral disease-modifying therapies in multiple sclerosis (MS) will have a significant impact on the evolving scenario of immunomodulatory treatments in MS where current therapies are all injectable. Reducing relapses in trials translates for individuals with MS into a therapeutic aim of stopping future events. Thus the possible absence of any perceived benefits to the individual together with the long disease course, variable outcome, and a younger age group affected in MS makes side effects the major issue. The use of disease-modifying therapies as a whole needs to be placed in the context of a widening therapeutic indication where the use of these therapies is being justified at an increasingly early stage and in pre-MS syndromes such as clinically isolated and radiologically isolated syndromes where no fixed disability is likely to have accumulated. The five oral therapies discussed (cladribine, fingolimod, laquinimod, BG-12, and teriflunomide) have just completed Phase III studies and some have just been licensed. New oral drugs for MS need to be placed within this evolving marketplace where ease of delivery together with efficacy and side effects needs to be balanced against the known issues but also the known long-term safety of standard injectables.

Evidence for abnormal tau phosphorylation in early aggressive multiple sclerosis.

Although progression in multiple sclerosis is pathologically dominated by neurodegeneration, the underlying mechanism is unknown. Abnormal hyperphosphorylation of tau is implicated in the aetiopathogenesis of some common neurodegenerative disorders. We recently demonstrated the association of insoluble tau with established secondary progressive MS, raising the hypothesis that its accumulation is relevant to disease progression. In order to begin to determine the temporal emergence of abnormal tau with disease progression in MS, we examined tau phosphorylation in cerebral tissue from a rare case of early aggressive MS. We report tau hyperphosphorylation occurring in multiple cell types, with biochemical analysis confirming restriction to the soluble fraction. The absence of sarcosyl-insoluble tau fraction in early disease and its presence in secondary progression raises the possibility that insoluble tau accumulates with disease progression.

A pragmatic approach to dealing with fingolimod-related lymphopaenia in Europe.

Dealing with treatment-related lymphopenia is now a routine, if not a daily, issue for neurologists and/or clinical nurse specialists managing patients with multiple sclerosis (MS) on diseasemodifying therapies (DMTs). Lymphopenia is a frequent occurrence on interferon-beta, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate and alemtuzumab, which are all licensed for use in MS. Circulating lymphocytes represent approximately 2% of the total lymphocyte population (Berzins et al., 1999) and are a poor indicator of the bodys total lymphocyte pool and function. This is particularly relevant to fingolimod, which is a non-depleting oral therapy and the first drug in new class that work via modulating sphingosine-1phosphate (S1P) biology (Chun and Hartung, 2010). After phosphorylation fingolimod acts as a high-affinity agonist on several G protein-coupled S1P receptors (Chun and Hartung, 2010). On binding fingolimod initially stimulates the S1P1 receptor before resulting in the aberrant internalization of the receptor that prevents the receptors from being recycled back to the cell surface membrane (Chun and Hartung, 2010). The loss of cell surface receptors renders lymphocytes unresponsive to the S1P gradient that is an obligatory signal for the egress of lymphocytes from the lymph nodes into the periphery (Chun and Hartung, 2010). Functional lymphocytes are therefore trapped in lymph nodes. Following fingolimod discontinuation, average counts exceeded the lower limit of normal range within 6–8 weeks, and were 80% of baseline values by three month (Francis et al., 2014; Kovarik et al., 2004), with a few cases taking much longer (Johnson et al., 2010). Lymphopenia in fingolimod-treated patients differs qualitatively to other forms of lymphopenia; therapeutic dosing with fingolimod reduces naïve and central memory T cells, but not effector memory T cells (Mehling et al., 2008). This occurs because naïve T cells and central memory T cells express the homing receptor CCR7, allowing them to recirculate to secondary lymphoid tissues on a regular basis and, thus, trapping of the cells by fingolimod in lymph nodes (Mehling, et al., 2008). Peripheral lymphopenia due to S1P modulators, such as fingolimod, is therefore biologically different to lymphopenia associated with other DMTs in that it does not indicate an absolute reduction in the total body lymphocyte

BG-12 and its potential for the prevention of relapse in multiple sclerosis

Multiple sclerosis (MS) arises from an immune attack on the central nervous system producing demyelination and axonal loss. Clinically the relapsing-remitting course is characterized by subacute onset of neurological symptoms usually with partial or complete recovery, while the progressive course, predominant in the later stages, is characterized by progressive disability in the absence of relapses. A number of disease-modifying treatments have been developed and are increasingly effective at targeting relapses. Early injectable therapies such as interferon and glatiramer acetate are only partially effective, but have a good safety record. Recently, natalizumab, an intravenous therapy, demonstrated increased effectiveness, but side effects complicate its use. The first oral therapy offering good efficacy and convenience, fingolimod, was approved in USA in 2010 and Europe in 2011. BG-12 is a potential novel oral therapy for MS, which has previously been used as a different formulation for psoriasis. It has anti-inflammatory and neuroprotective actions in vitro, which makes it a promising candidate for future therapies. Phase II studies showed that BG-12 reduced MRI inflammatory activity over placebo, which was confirmed in two Phase III studies indicating immune modulation may be its principal action rather than neuroprotection. In these studies, BG-12 reduced relapse rates consistently with variable effects on progression and few serious adverse events. With its favorable efficacy-tolerability profile, BG-12 could offer a substantial step forward for the care for subjects affected by relapsing MS.