Simonetta Galgani

Escalation to natalizumab or switching among immunomodulators in relapsing multiple sclerosis

Objective: To evaluate whether an escalation approach was more effective in suppressing clinical and magnetic resonance imaging (MRI) activity than switching among immunomodulators in relapsing–remitting multiple sclerosis (RRMS) patients. Methods: In this post-marketing, prospective, observational study in two Italian multiple sclerosis (MS) centres, a total of 285 RRMS patients who failed a first-line treatment with interferon beta (IFNβ) or glatiramer acetate (GA) were considered. Patients were subdivided according to the strategy adopted after the failure (defined as the occurrence of ≥2 relapses or 1 relapse with residual disability): the switching (SWI) group, i.e. those switched among different IFNβ formulations, or from IFNβ to GA and vice versa; and the escalating (ESC) group, i.e. those escalated to natalizumab. Proportions of patients free from different types of disease activity (relapses, sustained disability progression, new active lesions on MRI, or a combination of them) were calculated at 12 and 24 months. Since patients were not randomized to treatment group, propensity score (PS)-adjusted Cox regression models were built to control for several potential confounders. Results: At 12 months there were no differences between the two groups in proportions of patients free from relapse, disability progression, MRI activity, and combined activity. After 24 months we observed greater proportions of patients in the ESC than SWI group free from relapse (pu2009<u20090.0001), disability progression (pu2009=u20090.0045), MRI activity (pu2009=u20090.0003), and combined activity (pu2009<u20090.0001). PS-adjusted models confirmed these findings, with hazard ratios ranging from 0.38 to 0.56 favours the ESC group. Conclusion: We suggest that an escalation to natalizumab is more effective than switching among immunomodulators in RRMS patients who failed a first-line treatment.

Effect of steroids on Gd-enhancing lesions before and during recombinant beta interferon 1a treatment in relapsing remitting multiple sclerosis.

The aim of this study was to investigate whether a concomitant treatment with recombinant interferon beta la (rIFNβ-la) modifies the effect of steroids on the blood-brain barrier (BBB) in relapsing remitting MS patients, as evaluated by enhanced MRI of the brain. We evaluated 19 patients with a clinical relapse treated only with intravenous methylprednisolone (IVMP; 1 g daily for 6 days), and 10 patients who experienced a clinical relapse and were treated with IVMP (1 g daily for 6 days) during an rIFNβ-la treatment period. The number and volume of enhancing lesions were analyzed on four serial MR images obtained at monthly intervals (one scan before and three scans after IVMP treatment). A significant reduction in the mean number and volume of enhancing lesions was seen in the first scan after IVMP treatment in all patients. However, while persistently low enhancement was seen in the follow-up scans of patients treated with rIFNβ-la, a rebound effect (i.e., increase in the number and volume of gadolinium-enhancing lesions) was observed in the other patients during the follow-up. These data suggest that rIFNβ-la prolongs the beneficial effect of steroids on the BBB.

Natalizumab discontinuation in patients with multiple sclerosis: Profiling risk and benefits at therapeutic crossroads

Objective: The objective of this paper is to estimate the risk of reaching well-established disability milestones after withdrawal of natalizumab (NTZ) due to concern about the risk of progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS). Methods: Data from 415 patients with MS followed-up for six years after starting NTZ were collected from seven tertiary MS centers. The risk of disability worsening, i.e. reaching Expanded Disability Status Scale (EDSS) scores of 4.0 or 6.0, and the likelihood of experiencing a disability reduction of one EDSS point (or more), were assessed by propensity score-adjusted analyses in patients who discontinued and in those still on treatment at the end of follow-up. Results: A total of 318 patients who received standard NTZ treatment without experiencing evidence of disability worsening in the first two years were included in the six-year follow-up analysis, with 196 (61.6%) still on treatment and 122 (38.4%) discontinuing after a median time of 3.5 years. Patients in the discontinuing group had a more than two-fold increased risk of disability worsening (p = 0.007), and a 68% decreased likelihood of experiencing disability reduction (p = 0.009) compared with the continuing group. Conclusion: While discussing the overall risk/benefit profile of NTZ, patients should be advised that, in case of treatment discontinuation, the risk of disability worsening is one in three, and increases to one in two if the EDSS score at NTZ start is above 3.0.

Determinants of Gd-enhanced MRI response to IFN-β-1a treatment in relapsing-remitting multiple sclerosis

The decision to use interferon beta (IFN-b) as a treatment for relapsing-remitting multiple sclerosis (RRMS) is based on both clinical characteristics and course of the disease. To better identify the profile of responders, the relationships between baseline clinical/MRI characteristics and therapeutical response was analyzed in 49 patients with RRMS randomly assigned to receive subcutaneously 3 or 9 MIU of IFN-b-1a. The therapeutical response was evaluated as a per cent change in the mean number and volume of monthly Gd-enhancing lesions in both first (early response) and second (late response) 6-month period of treatment, compared to the 6-month pre-treatment period. A better early response was seen in patients with a lower number of relapses during the pre-treatment period, while the late response was favourably influenced by a lower baseline EDSS and the high dose. Our findings suggest that the effect of IFN-b-1a on disease MRI activity is dose-related and dependent on the relapse rate and the level of disability before treatment.

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.

Prevalence of multiple sclerosis in the Lazio region, Italy: use of an algorithm based on health information systems

Compared with other areas of the country, very limited data are available on multiple sclerosis (MS) prevalence in Central Italy. We aimed to estimate MS prevalence in the Lazio region and its geographical distribution using regional health information systems (HIS). To identify MS cases we used data from drug prescription, hospital discharge and ticket exemption registries. Crude, age- and gender-specific prevalence estimates on December 31, 2011 were calculated. To compare MS prevalence between different areas within the region, we calculated age- and gender-adjusted prevalence and prevalence ratios using a multivariate Poisson regression model. Crude prevalence rate was 130.5/100,000 (95xa0% CI 127.5–133.5): 89.7/100,000 for males and 167.9/100,000 for females. The overall prevalence rate standardized to the European Standard Population was 119.6/100,000 (95xa0% CI 116.8–122.4). We observed significant differences in MS prevalence within the region, with estimates ranging from 96.3 (95xa0% CI 86.4–107.3) for Latina to 169.6 (95xa0% CI 147.6–194.9) for Rieti. Most districts close to the coast showed lower prevalence estimates compared to those situated in the eastern mountainous area of the region. In conclusion, this study produced a MS prevalence estimate at regional level using population-based health administrative databases. Our results showed the Lazio region is a high-risk area for MS, although with an uneven geographical distribution. While some limitations must be considered including possible prevalence underestimation, HIS represent a valuable source of information to measure the burden of SM, useful for epidemiological surveillance and healthcare planning.

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.

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.

Early transient asymptomatic neutropenia associated with alemtuzumab treatment in multiple sclerosis: a case report

Alemtuzumab is a humanized monoclonal antibody approved for the treatment of ‘active’ relapsing-remitting multiple sclerosis (RRMS) as defined by clinical or imaging features [1, 2]. It selectively targets the CD52, a surface antigen highly expressed on circulating lymphocytes, thus leading to long-lasting T and B-cell depletion. We here reported a case of asymptomatic leukopenia with neutropenia detected ~ 1 month after the first alemtuzumab course with spontaneous resolution. A 44-year-old Caucasian woman with RRMS was initially treated with interferon beta-1a (2004–2009), and then with natalizumab (2010–2012), suspended after 24 infusions for increased risk of progressive multifocal leukoencephalopathy. Afterward she was treated with fingolimod (2012–2017), which had been discontinued due to a severe relapse and persistent magnetic resonance activity documented in repeated brain scans. She received her first alemtuzumab course (12 mg/day for 5 days) since March 27, 2018, ~ 4 months after the last fingolimod dose. At that time, her white blood cell count (WBC), absolute neutrophil count (ANC), and absolute lymphocyte count (ALC) were normal. Standard antiviral prophylaxis (acyclovir 200 mg twice per day) was started on the first day of infusion and continued for 4 weeks. A blood test 3 days after the last infusion, carried out due to persistent skin rash, documented only lymphopenia (WBC 5040/ μL, ANC 4910/μL, ALC 10/μL). A subsequent blood test, performed ~ 1 month later, revealed grade 4 leukopenia and grade 3 neutropenia (WBC 850/μL, ANC 760/μL, ALC 10/ μL), with normal red blood cells and platelet count. She was being afebrile with no sign, symptom, or laboratory test suggestive of infection. Other causes for neutropenia, including viral infections and autoimmune reactions, were ruled out by extensive serological examinations and chest X-ray. Following hematological and infectious disease consultations, the patient was promptly treated with prophylaxis therapy based on fluconazole (200 mg daily), amoxycillin (3000 mg daily), and acyclovir (200 mg daily). These prophylaxis treatments were suspended ~ 2 weeks later, following normalization of blood values (WBC 2580/μL, ANC 2160/μL, ALC 70/μL). The last blood count examination (June 04, 2018) confirmed normal values, except for the expected lymphopenia (WBC 4250/μL, ANC 3810/μL, ALC 50/μL; see Fig. 1). To our knowledge, this is the first case report of a patient with RRMS who developed an alemtuzumab-related, totally asymptomatic leukopenia with neutropenia, which resolved spontaneously. Mild neutropenia was reported in 20–25% of subjects enrolled in clinical trials on alemtuzumab; however, the incidence of grade 3–4 neutropenia was < 1% in the first year and < 2% of patients in the second year of follow-up [3]. In post-marketing setting, three cases of febrile neutropenia have been reported, occurring 4–6 weeks after the last alemtuzumab infusion, two of whom resolved after G-CSF treatment [4] and the third died of staphylococcal sepsis [5]. While severe neutropenia is an uncommon adverse event in RRMS, > 20% of patients with haematologic malignancies develop transient neutropenia following alemtuzumab treatment, typically 3–8 weeks after the first cycle, at dosages equivalent to those for RRMS (60 mg) [6]. The exact mechanism of early neutropenia associated with alemtuzumab is still not fully understood. Hematopoietic stem * Luca Prosperini luca.prosperini@gmail.com