Sexual Dysfunction in People with Multiple Sclerosis: The Role of Disease Severity, Illness Perception, and Depression.

Despite being a common issue in people with multiple sclerosis (pwMS), sexual dysfunction is still underinvestigated. This work aims to assess the potential determinants of sexual dysfunction in pwMS by considering its relationship with disease severity (in terms of global disability), illness perception, and depressive symptoms. In this multicenter study, 1010 pwMS responded to an online survey. A serial mediation model considering negative illness perception and depressive symptoms as mediators of the relationship between disease severity and sexual dysfunction was conducted using the SPSS PROCESS Macro with bias-corrected bootstrapping (5000 samples). Disease severity exerts an indirect effect on sexual dysfunction via illness perception, both independently and through depressive symptoms. However, the results indicated that illness perception plays a more crucial role in sexual dysfunction in pwMS with mild disability than in pwMS with moderate-severe disability. This study suggests that higher disability increases its magnitude by enhancing negative illness perception, that, in turn, affects sexual dysfunction both directly and through depressive symptoms, especially in pwMS with mild disability. Modulating the effect of illness perception by favoring adaptive coping strategies might represent a valid approach to mitigate sexual dysfunction symptoms in MS.

REal-World effectIveNess of claDribine for patients with multiple sclerosis: a Sicilian multicentric experience (REWIND study).

BACKGROUND: cladribine tablets is a highly effective option for the treatment of relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: to evaluate the effectiveness of cladribine in a real-world setting. METHODS: this prospective real-world study consecutively screened all RRMS patients from seven different MS centers in Sicily (Italy), who completed the 2-year treatment course of cladribine tablets in the period between 11th March 2019 and 31st October 2021. Data about Expanded Disability Status Scale (EDSS), relapses, previous treatments, adverse events (AEs) and magnetic resonance imaging (MRI) were collected. Patients who were previously treated with other DMTs were further stratified in moderately active treatment (MAT) and highly active treatment (HAT) patients. RESULTS: a total of 217 patients, (70% women, with mean age of 38.4 ± 11.3 years), were enrolled. Fifty patients (23.0%) were naïve to treatment and 167 (77%) switched from another disease modifying therapies. After the second year of treatment, about 80% of were EDSS progression free, 88% remained relapse-free at T24, and 48% of patients were MRI activity-free. Kaplan Meier analyses showed significant differences between MT and HAT in terms of time to first clinical relapse (HR: 2.43, IC 1.02 - 5.76; p=0.04), time to the first new T1-gadolinium enhancing lesion (HR: 3.43, IC 1.35 - 8.70; p= 0.009) and time to MRI worsening (HR: 2.42, IC 1.15 - 5.09; p= 0.02). CONCLUSION: this study confirmed that cladribine is an effective treatment for MS, in particular in naïve patients and in those who have switched from MATs.

Factors driving delayed time to multiple sclerosis diagnosis: Results from a population-based study.

BACKGROUND: Multiple sclerosis (MS) is a highly complex chronic inflammatory disease, in which a diagnostic delay could reduce the available therapeutic options. Our aim was to identify factors contributing to diagnostic delay in a MS population living in the municipality of Biancavilla. METHODS: This retrospective population-based study consecutively selected patients with MS diagnosed from 1992 to 2018 and resident in the city of Biancavilla. Socio-demographic and clinical data were collected through the iMed database. Date of final MS diagnosis was obtained and diagnostic delay was calculated. RESULTS: A total of 70 patients (66.7% women) were found affected by MS according to the 2011 McDonald criteria in the municipality of Biancavilla in the period between 2005 and 2010. The mean diagnostic delay in the MS cohort of Biancavilla was 33.8 ± 56 months [median 19.5, range 1-315]. The multivariate logistic regression confirmed that age ≥ 40 years, lower educational level (1-5 years) and motor symptoms at onset were associated to longer diagnostic delay. CONCLUSION: In this population-based study a mean delay of about 30 months occurred between initial symptoms and the MS diagnosis. Older age at onset, lower education level and motor symptoms at onset were associated to longer MS diagnostic delay.

Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis Patients: Monocentric Case Series and Systematic Review of the Literature.

Multiple sclerosis (MS) is a chronic, inflammatory and immune-mediated disease of the central nervous system (CNS), commonly affecting young adults and potentially associated with life-long disability. About 14 disease-modifying treatments (DMTs) are currently approved for the treatment of MS. However, despite the use of highly effective therapies, some patients exhibit a highly active disease with an aggressive course from onset and a higher risk of long-term disability accrual. In the last few years, several retrospective studies, clinical trials, meta-analyses and systematic reviews have investigated autologous hematopoietic stem cell transplantation (AHSCT) as a possible therapeutic option in order to address this unmet clinical need. These studies demonstrated that AHSCT is a highly efficacious and relatively safe therapeutic option for the treatment of highly active MS. Particularly, over recent years, the amount of evidence has grown, with significant improvements in the development of patient selection criteria, choice of the most suitable transplant technique and clinical experience. In this paper, we present six patients who received AHSCT in our MS center and we systematically reviewed recent evidence about the long-term efficacy and safety of AHSCT and the placement of AHSCT in the rapidly evolving therapeutic armamentarium for MS.

Reliability of televisits for patients with mild relapsing-remitting multiple sclerosis in the COVID-19 era.

BACKGROUND: Evidence of the cost-effectiveness of telemedicine (TM) for the management of Multiple Sclerosis (MS) has been provided recently. However, some doubts persist about the accuracy of neurological examinations performed remotely. OBJECTIVES: This study investigated the reliability of neurological evaluations performed through TM in mild MS patients as compared with standard in-person visits. METHODS: In total, 76 patients with relapsing-remitting MS and Expanded Disability Status Scale (EDSS) ≤ 3.5 were consecutively recruited. Of them, 40 patients (52.6%) accepted to undergo both in-person and TM evaluations with independent examiners within 48 h. We alternatively asked patients to assure or not the presence of a caregiver during TM visits. A satisfaction questionnaire was administered to all participants. RESULTS: The inter-rater agreement attributed by two independent neurologists during TM visit was high (κ > 0.80) for EDSS and Functional Systems (FS) scores. Moderate agreement between TM and in-person evaluations emerged for pyramidal (κ = 0.57; p < 0.001), brainstem (κ = 0.57; p < 0.001), bowel and bladder (κ = 0.54; p < 0.001) and sensory (κ = 0.51; p < 0.001) FS scores, higher in patients providing the support of a caregiver. A good reliability was reported for EDSS scores computed during remote and in-person visits (ICC = 0.83; 95% CI 0.70-0.91; p < 0.001). CONCLUSIONS: Despite the complexity of neurological examination, TM could be useful in monitoring MS patients with low disability.

Rituximab for the treatment of multiple sclerosis: a review.

In the last decades, evidence suggesting the direct or indirect involvement of B cells on multiple sclerosis (MS) pathogenesis has accumulated. The increased amount of data on the efficacy and safety of B-cell-depleting therapies from several studies has suggested the addition of these drugs as treatment options to the current armamentarium of disease modifying therapies (DMTs) for MS. Particularly, rituximab (RTX), a chimeric monoclonal antibody directed at CD20 positive B lymphocytes resulting in cell-mediated apoptosis, has been demonstrated to reduce inflammatory activity, incidence of relapses and new brain lesions on magnetic resonance imaging (MRI) in patients with relapsing-remitting MS (RRMS). Additional evidence also demonstrated that patients with progressive MS (PMS) may benefit from RTX, which also showed to be well tolerated, with acceptable safety risks and favorable cost-effectiveness profile.Despite these encouraging results, RTX is currently approved for non-Hodgkin's lymphoma, chronic lymphocytic leukemia, several forms of vasculitis and rheumatoid arthritis, while it can only be administered off-label for MS treatment. Between Northern European countries exist different rules for using not licensed drug for treating MS. The Sweden MS register reports a high rate (53.5%) of off-label RTX prescriptions in relation to other annually started DMTs to treat MS patients, while Danish and Norwegian neurologists have to use other anti-CD20 drugs, as ocrelizumab, in most of the cases.In this paper, we review the pharmacokinetics, pharmacodynamics, clinical efficacy, safety profile and cost effectiveness aspects of RTX for the treatment of MS. Particularly, with the approval of new anti-CD20 DMTs, the recent worldwide COVID-19 emergency and the possible increased risk of infection with this class of drugs, this review sheds light on the use of RTX as an alternative treatment option for MS management, while commenting the gaps of knowledge regarding this drug.

Natalizumab administration in multiple sclerosis patients during active SARS-CoV-2 infection: a case series.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) caused by the new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become a pandemic, affecting the therapeutic management for Multiple Sclerosis (MS). Any decision regarding the discontinuation of high-potency agents for moderate and highly active MS should be carefully evaluated, taking into account the potential risk of rebound of the disease. In particular, no data about clinical outcome of patients with MS receiving Natalizumab (NTZ) during active COVID-19 infection have been reported yet. CASES PRESENTATION: We reported on 6 patients treated with NTZ for relapsing MS during active COVID-19 infection, who recovered without reporting any worsening or new symptoms. Most of the patients were asymptomatic, with the exception of one patient who had a slight worst COVID-19 clinical course. No patients received O2-therapy or required intensive care. No neurological complications were observed. CONCLUSIONS: This paper reported the clinical outcome of patients with MS receiving NTZ during active COVID-19 infection. This case series suggests that treatment with NTZ during pandemic is relatively safe and might be continued in selected patients who are infected by COVID-19, thereby reducing the risk of MS disease rebound.

An update on the pharmacological management of pain in patients with multiple sclerosis.

INTRODUCTION: The prevalence of pain in Multiple Sclerosis (MS) is estimated to be between 29-86% depending on various stages of the disease. According to a recent mechanism-based classification, MS pain syndromes include ongoing extremity pain, trigeminal neuralgia, and Lhermitte's phenomenon, painful tonic spasms and spasticity pain, pain associated with optic neuritis, musculoskeletal pain, migraine, and treatment-induced pain. AREA COVERED: Pharmacological approaches for MS pain include anticonvulsants, antidepressants, botulinum toxin, cannabinoids, muscle relaxants, opioid analgesics, and intrathecally administered baclofen. It has been reported that pharmacological treatments have poor efficacy and alarming side effects. For these reasons, non-pharmacological interventions, either alone or in combination with pharmacological treatments are commonly used in clinical practice. Examples of these interventions include electrical or chemical neurostimulation therapy, exercise, and psychological approaches. This is discussed in more detail herein. EXPERT OPINION: The management of MS pain can be challenging due to the natural course of the disease and the lack of a definite cure. Recommendations based on rigorous scientific methods for MS pain treatment are unavailable. Thus, clinicians should consider available treatment regimens based on efficacy, safety, cost, and the clinical complexity of the patient. The use of therapeutic approaches combining pharmacological and non-pharmacological treatments may help to reduce the risk of overuse and mitigate the complaint of simultaneous and multiple therapies.

Conversion to Secondary Progressive Multiple Sclerosis: Patient Awareness and Needs. Results From an Online Survey in Italy and Germany.

Background: Few studies have investigated the experiences of patients around the conversion to secondary progressive multiple sclerosis (SPMS). ManTra is a mixed-method, co-production research project conducted in Italy and Germany to develop an intervention for newly-diagnosed SPMS patients. In previous project actions, we identified the needs and experiences of patients converting to SPMS via literature review and qualitative research which involved key stakeholders. Aims: The online patient survey aimed to assess, on a larger and independent sample of recently-diagnosed SPMS patients: (a) the characteristics associated to patient awareness of SPMS conversion; (b) the experience of conversion; (c) importance and prioritization of the needs previously identified. Methods: Participants were consenting adults with SPMS since ≤5 years. The survey consisted of three sections: on general and clinical characteristics; on experience of SPMS diagnosis disclosure (aware participants only); and on importance and prioritization of 33 pre-specified needs. Results: Of 215 participants, those aware of their SPMS diagnosis were 57% in Italy vs. 77% in Germany (p = 0.004). In both countries, over 80% of aware participants received a SPMS diagnosis from the neurologist; satisfaction with SPMS disclosure was moderate to high. Nevertheless, 28-35% obtained second opinions, and 48-56% reported they did not receive any information on SPMS. Participants actively seeking further information were 63% in Germany vs. 31% in Italy (p < 0.001). Variables independently associated to patient awareness were geographic area (odds ratio, OR 0.32, 95% CI 0.13-0.78 for Central Italy; OR 0.21, 95% CI 0.08-0.58 for Southern Italy [vs. Germany]) and activity limitations (OR 7.80, 95% CI 1.47-41.37 for dependent vs. autonomous patients). All pre-specified needs were scored a lot or extremely important, and two prioritized needs were shared by Italian and German patients: "physiotherapy" and "active patient care involvement." The other two differed across countries: "an individualized health care plan" and "information on social rights and policies" in Italy, and "psychological support" and "cognitive rehabilitation" in Germany. Conclusions: Around 40% of SPMS patients were not aware of their disease form indicating a need to improve patient-physician communication. Physiotherapy and active patient care involvement were prioritized in both countries.

An update on the safety of treating relapsing-remitting multiple sclerosis.

Introduction: In the last 20 years the armamentarium for multiple sclerosis (MS) treatment has been enriched from an increasingly wider variety of new drugs in order to reach a better control of the disease with a better patient compliance. Areas covered: With this great variety of therapeutic options, physicians may face new and major challenges. The huge amount of data from pilot studies and real-life settings showed that the first-line therapies have a better safety profile. On the other hand, the risks associated with newer drugs, with more selective mechanism of action and targeting specific pathways of MS pathophysiology, are not yet fully established. In particular, real-life use of these advanced drugs has raised important safety issues as long-term effects and potential risks are not yet known and remain to be carefully evaluated. Expert opinion: No time like the present, the physician faces new and major challenges in order to choose the best available therapy for MS. With the increasing number of drugs for treating MS and the lack of safety data, observational studies and post-marketing surveillance activities are crucial in order to improve the knowledge about the safety profile of these drugs and the therapeutic management in clinical practice settings.

Cancer Risk and Multiple Sclerosis: Evidence From a Large Italian Cohort.

Introduction: The complexity of understanding cancer risk in MS is increased by inconsistencies in study design, and the lack of age-, sex-, and ethnicity-specific risk estimates. Aims of our study were to estimate the incidence of cancers in the MS population of Catania (Italy) and to evaluate the impact of disease-modifying treatments (DMTs) in cancer risk. Materials and Methods: We screened 2,730 PwMS according to the MS criteria of Mc Donald 2010 referring to MS center of Catania in the period between 2003 and 2013. We matched database of MS patients with the Integrated Cancer of Catania-Messina-Siracusae-Enna. We calculated age and sex specific standardized incidence ratios (SIR) and the relative risk (RR) of developing cancer in MS patients treated with at least two different DMTs compared to who received one or no treatment. Results: Out of 2,730, 1,180 MS patients (67.1% females; mean age 41.2 ± 12.9) were enrolled. We found 36 cancers. Global SIR was 1.18 (CI95% 0.78-1.58), with a significantly higher risk in men with a range age of 20 to 50 years [2.84; (CI95% 1.59-4.09)] and in women over 50 years [1.82 (CI95% 1.08-2.55)]. RR of developing cancer was 1.99 (CI95% 1.14-3.45) in MS patients switching one DMT and 3.38 (CI95% 1.83-6.22) in who switched at least twice. Discussion: Our results demonstrated that cancer risk was not increased in our MS population; but age and sex different distribution may partly drive cancer risk. Higher cancer risk in MS patients switching more than two DMTs should take into account in treatment decision making.

Effectiveness and safety of Rituximab in demyelinating diseases spectrum: An Italian experience.

BACKGROUND: Rituximab (RTX), a monoclonal antibody targeting the CD20+ B lymphocytes, deserves major attention as therapeutic option in the treatment of demyelinating disorders of the central nervous system (DDCNS). We reported our clinical experience with the use of RTX in terms of efficacy and safety in persons suffering from DDCNS. METHODS: An Italian single-center observational analysis of patients who underwent RTX treatment between 2011 and 2017 was performed at MS center of Catania, Italy. No evidence of disease activity (NEDA) was applied to evaluate the response to RTX. CD19+ and CD20+ counts were collected along therapy. RTX-related adverse events were recorded. RESULTS: Eleven patients with MS, four with NMOSD and two with NMO were enrolled. Out of them, 4/17 were naïve to previous treatments. According to NEDA status, 11/17 got NEDA3 status at the follow-up. Six patients had relapses (two had a single relapse and four had multiple relapses). One patient with primary progressive MS and one with relapsing remitting MS stopped RTX, the last one for severe lymphopenia. CONCLUSIONS: RTX showed efficacy to impact DDCNS worsening with an acceptable safety profile.