Shalom Haggiag

Interferon-β-1a in relapsing-remitting multiple sclerosis: effect on hypointense lesion volume on T1 weighted images

OBJECTIVE Recently, a strong correlation between the increase in hypointense lesion load on T1 weighted spin echo images, and the increase in disability was reported. Although the effect of interferon-β has been demonstrated both in reducing exacerbation rate, frequency of enhancing lesions, and accumulation of disease burden on T2 weighted images, the impact on the accumulation of hypointense lesions has not yet been evaluated. The aims of the present study were: (a) to assess for the first time the effect of interferon-β-1a on T1 weighted MRI hypointense lesion volume; and (b) to evaluate the relation between changes on hypointense, hyperintense, and enhancing lesion volume before and during interferon-β-1a treatment in relapsing-remitting multiple sclerosis. METHODS After a baseline scan and 6 month pretreatment period, 67 patients with relapsing-remitting multiple sclerosis were treated with interferon-β-1a by subcutaneous injection three times a week during a 12 month treatment period. All patients had MRI every month during the 6 month pretreatment period and for the first 9 months of the treatment period. A final MRI was also performed at the end of the 12 month treatment period. RESULTS There was a significant increase in the mean hyperintense lesion volume during the pretreatment phase (6 months) and a slight decrease during the treatment period (12 months), whereas the hypointense lesion volume increased significantly before treatment and remained substantially stable during treatment. There was a significant correlation between changes in hypointense and hyperintense lesion volume during the observation period, but not during treatment. The monthly mean volume of Gadolinium-DTPA enhancing lesions was significantly higher during the pretreatment than the treatment period, and the enhancing lesion volume correlated with changes of hyperintense and hypointense lesion volumes only during the observation period. CONCLUSION These data suggest that interferon-β-1a has a stabilising effect on T1 weighted hypointense lesion volume.

Efficacy and safety of laquinimod in multiple sclerosis: current status

Laquinimod is a novel immunomodulatory agent, in development as a potential disease-modifying treatment for multiple sclerosis (MS). Structurally related to linomide, its pharmacological predecessor, laquinimod combines anti-inflammatory and possibly clinically relevant neuroprotective effects with the convenience of oral administration. In this review we aim to highlight the immunomodulatory and neuroprotective effects of laquinimod, and to describe its effects in animal models of MS. Furthermore, we focus on current results of clinical studies in MS. Randomized, controlled clinical trials in relapsing MS demonstrate a dose–response effect on disease activity, measured by reduced clinical relapse rate, reduced number of brain MRI active lesions, as well as on sustained disability and brain atrophy. Laquinimod has a favourable tolerability and safety profile. A new phase III study, recently completed, will soon provide further details on the therapeutic potential of this drug. Laquinimod is a promising emerging treatment for relapsing–remitting MS that may provide a new therapeutic option in the near future.

Real-world effectiveness of natalizumab and fingolimod compared with self-injectable drugs in non-responders and in treatment-naïve patients with multiple sclerosis

In this independent, multicentre post-marketing study we directly compared the effectiveness of natalizumab (NTZ), fingolimod (FNG) and self-injectable drugs (INJ), in non-responders to first immunomodulating treatment and in highly active treatment-naïve patients with multiple sclerosis. As main outcome measure we considered the proportions of patients with no evidence of disease activity (NEDA-3), defined as absence of relapses, disability worsening and radiological activity. A total of 567 non-responders to interferon beta (IFNB) or glatiramer acetate (GA) [dataset A] and 216 highly active treatment-naïves [dataset B] were followed up to 24xa0months from the beginning of NTZ, FNG or INJ, i.e. switching from IFNB to GA or viceversa (in the case of non-responders) or starting high-dose IFNB (in the case of highly active treatment-naïves). Propensity score matching in a 1:1:1 ratio was used to select only patients with similar baseline characteristics, retaining 330 and 120 patients in dataset A and B, respectively. In dataset A, the 24-month proportion with NEDA-3 was greater in both NTZ group (67%) and FNG group (42%) than in INJ group (35%) (pxa0≤xa00.016); however, NTZ was superior to FNG in promoting the attainment of NEDA-3 status (pxa0=xa00.034). In dataset B, the 24-month proportion with NEDA-3 was greater in NTZ group (75%) and FNG group (67%) than in INJ group (40%), but the small cohort sizes most likely prevented the detection of any statistically significant difference. Our study provides real-world evidence that NTZ was more effective than both FNG and INJ in non-responders, while it could seem that, in highly active treatment-naïves, NTZ was as effective as FNG and both were superior to INJ.

Painful and involuntary multiple sclerosis

Introduction: Pain, dysphagia, respiratory problems, sexual and cardiovascular dysfunctions may occur in patients with MS. Areas covered: In the present review, we attempt to summarize the current knowledge on the impact pain, dysphagia, respiratory problems, sexual and cardiovascular dysfunctions have in patients with MS. Expert opinion: To effectively manage MS, it is essential that these symptoms are recognized as early as possible and treated by a rehabilitative multidisciplinary approach, based on proven scientific evidence.

Drugs in clinical development for multiple sclerosis: focusing on anti-CD20 antibodies

Introduction: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), traditionally considered to be an autoimmune disease. Despite the standard of care for patients with MS is significantly improved in recent years, there is still room for improvement in terms of effectiveness and also compliance. Areas covered: The continuous improvements of our understanding of the pathophysiological changes that occur in MS have translated into many novel therapeutic agents at different stages of development. A number of therapies for MS are in advanced development and likely to be available soon. Along with these, we have also seen the appearance of a group of drugs considered together as a consequence of their similar design: the monoclonal antibodies (mAbs). Here, the focus will be on reviewing results that have emerged from a better clarification of MS pathogenesis to clinical trials of different anti-CD20 mAbs. Expert opinion: The decision to switch established patients from well-known drugs to either new formulations or new agents will be made on balancing efficacy and tolerability of the existing treatments. Safety seems increasingly likely to become a key factor.

Early-onset optic neuropathy as initial clinical presentation in SPG7.

Mutations in SPG7-Paraplegin (MIM 602783) have first been associated with a rare autosomal recessive form of hereditary spastic paraparesis (HSP) [1]. Over the past 15 years, dominant and recessive mutations in SPG7 have been increasingly recognized and associated with cerebellar involvement and subtentorial atrophy at MRI [2, 3], optic neuropathy [4], progressive external ophthalmoplegia and ptosis [5], and supranuclear palsy [6]. In the vast majority of cases, the age at onset of motor symptoms ranges from 10 to 45 years [3] and ancillary features usually occur later. We report a 43-year-old man, born to healthy non consanguineous parents, who presented severe visual problems since childhood, diagnosed as congenital optic atrophy. His visual acuity slowly worsened over several years but remained his only complaint. He first sought neurological expert consultation after age 30, when he started complaining of slowly progressive walking difficulties and urinary urgency. At the age of 43, neurological examination showed moderate spastic paraparesis (SPRS score was 14 [7]), brisk reflexes as well as some difficulties in tandem walking, gaze-evoked nystagmus, slight intentional hand tremor but no sensory disturbance. Visual acuity was 1/100 bilaterally; at fundus examination, pale optic disks were observed. Optical Coherence Tomography (OCT) scan showed bilateral reduction of macular thickness, due to selective depletion of ganglionic cells, diffuse and severe reduction of papillar nervous fibers. Brain MRI showed marked optic nerves and chiasm as well as mild cerebellar atrophy (Fig. 1). After obtaining written informed consent, molecular studies identified the c.538[A/p.V180M in compound heterozygosity with the c.1045[A/p.G349S in SPG7, while failed to show any change in OPA1, MFN2 and AFG3L2. Both mutations have been previously reported as disease-causative [4]. MtDNA mutations usually associated with Leber Hereditary Optic Neuropathy (LHON) were also excluded. Interestingly, the patient’s sister, aged 42 years, who carries the heterozygous c.538[A/p.V180M mutation, shows signs of mild cerebellar involvement and bilateral mild depletion of ganglionic cells at OCT scan. Moreover, the patient’s father, also carrying the same mutation, was found to have mild signs of cerebellar involvement but no changes at the OCT scan. This raises the possibility of a partially dominant pattern of transmission of the c.538[A/p.V180M mutation as reported already for the c.1232A[C/p.D411A [4]. Optic neuropathy is a relatively frequent clinical finding associated with SPG7 mutations, usually presenting C. Marcotulli L. Leonardi C. Casali (&) Department of SBMC, Sapienza University Rome, Rome, Italy e-mail: carlo.casali@uniroma1.it

Safety and Efficacy of Dimethyl Fumarate in Multiple Sclerosis: An Italian, Multicenter, Real-World Study

BackgroundTwo phase III trials have demonstrated the clinical and radiological efficacy of delayed-release dimethyl fumarate (DMF) in relapsing-remitting multiple sclerosis (RRMS). However, data on its safety and effectiveness in real-world practice are still limited.ObjectivesThe aim of our study was to explore the safety and tolerability profile of DMF in RRMS. We also tried to identify individual variables associated with better clinical and radiological outcomes.MethodsWe collected the clinical and magnetic resonance imaging (MRI) data of patients with RRMS who started DMF between 2012 and 2017 in seven MS clinics in central Italy. We first evaluated DMF discontinuation rates and the incidence of adverse events and side effects. We then assessed the annualized relapse rate (ARR), the number of patients with clinical relapses or disability worsening and the presence of radiological activity. Third, we investigated which baseline variables were associated with clinical and radiological outcomes.ResultsWe collected data for 1089 patients with a mean on-treatment follow-up of 17u2009±u20098xa0months; 331 (30.4%) of these patients were treatment naïve. In total, 210 (19.5%) patients discontinued DMF mainly because of poor tolerability (nu2009=u2009103) and disease activity (nu2009=u200963), and 166 (16.5%) patients presented with lymphopenia. The ARR reduced from 0.55 to 0.13. Mean change in Expanded Disability Status Scale (EDSS) score was 0.08u2009±u20090.44 per year. The occurrence of clinical and/or radiological activity during follow-up was associated with younger age [hazard ratio (HR) 0.97; pu2009<u20090.001], higher EDSS score (HR 1.18; pu2009<u20090.001), greater number of Gd-enhancing lesions at baseline scan (HR 1.14; pu2009=u20090.003) and prior exposure to MS treatments (HR 1.43; pu2009=u20090.02).ConclusionThis post-marketing data confirms the short-term safety, tolerability and effectiveness of DMF, supporting its use as an early treatment in MS.

Extratemporal herpes encephalitis during natalizumab treatment: A case report

Herpes simplex virus encephalitis (HSE) is a rare but often fatal disease if left untreated. MRI typically shows the characteristic findings of medial temporal lobe and insular involvement, while diagnosis in confirmed by CSF PCR. In immunocompromised state, HSE may have atypical clinical and radiological features. We report a MS patient under natalizumab treatment with HSE, who presented with MRI lesions exclusively in the right parietal lobe. The patient was timely started on acyclovir resulting in marked improvement. A high index of suspicion for HSE should be maintained when a patient presents with fever and extratemporal lesions, even more in immunocompromised subjects.

Fingolimod vs dimethyl fumarate in multiple sclerosis: A real-world propensity score-matched study

Objective To directly compare fingolimod (FNG) and dimethyl fumarate (DMF) on no evident disease activity (NEDA) status in patients with relapsing-remitting multiple sclerosis (RRMS) from 7 multiple sclerosis outpatient clinics in Central Italy. Methods We analyzed data of patients with RRMS who started an oral agent, namely DMF or FNG, either as first treatment (naives) or after switching from self-injectable drugs (switchers). We performed a propensity score (PS)–based nearest-neighbor matching within a caliper of 0.05 to select patients with homogeneous baseline characteristics. Pairwise censoring was adopted to adjust for difference in length of follow-up between the 2 treatment groups. Comparisons were then conducted in matched samples with Cox models (stratified by center) with NEDA-3 as the main outcome. NEDA-3 was defined as no relapses, no disability worsening, and no MRI activity. Results Overall, 483 and 456 patients eligible for analysis started on FNG and DMF, respectively. The PS-matching procedure retained a total of 550 patients (275 per group). After a median on-study follow-up of 18 months, the proportions of patients with NEDA-3 were similar (FNG 73%, DMF 70%; hazard ratio [HR] 0.74, p = 0.078). Subgroup analyses showed a comparable effectiveness of the 2 drugs in naives (n = 170, HR 1.15, p = 0.689), whereas FNG was superior to DMF in the achievement of NEDA-3 status among switchers (n = 380, HR 0.57, p = 0.007). Conclusion We found no significant difference between FNG and DMF on NEDA-3 status, while subgroup analyses suggest the superiority of FNG over DMF in patients switching from self-injectable drugs. Classification of evidence This study provides Class IV evidence that for patients with RRMS, DMF and FNG have comparable efficacy in treatment-naive patients and that FNG is superior to DMF in patients switching from self-injectable drugs.

Abortion induces reactivation of inflammation in relapsing-remitting multiple sclerosis

Objective To investigate clinical and radiological outcomes of women with relapsing-remitting multiple sclerosis (RRMS) undergoing abortion. Methods An independent, multicentre retrospective study was conducted collecting data from eight Italian MS centres. We compared the preconception and postabortion annualised relapse rate (ARR) and number of Gadolinium enhancing (Gd+) lesions, by analyses of covariance. Variables associated with postabortion clinical and MRI activity were investigated using Poisson regression models; each abortion was considered as a statistical unit. Results From 1995 to 2017, we observed 188 abortions (17 elective) in 153 women with RRMS. Abortions occurred after a mean time of 9.5 (4.4) weeks from estimated conception date. In 86 events out of 188, conception happened during treatment with disease modifying drugs. The mean postabortion ARR (0.63±0.74) was significantly increased (p=0.037) compared with the preconception year (0.50±0.71) as well as the postabortion mean number of new Gd+ lesions (0.77±1.40 vs 0.39±1.04; p=0.004). Higher likelihood of relapses was predicted by higher preconception ARR, discontinuation of preconception treatment and elective abortion; the occurrence of new Gd+ lesions was associated with higher preconception number of active lesions, discontinuation of preconception treatment, shorter length of pregnancy maintenance and elective abortion. Conclusions Abortion was associated with clinical and radiological inflammatory rebound remarkably in the first 12 months postevent. Deregulated proinflammatory processes arising at the early stages of pregnancy might play a role both in MS reactivation and abortion. Women with MS should be counselled about these risks of abortion and followed up accordingly.