The HLA-DRB1 risk alleles for multiple sclerosis are differentially expressed in blood cells of patients from Southern Italy.

HLA gene expression has an important role in the autoimmune disease predisposition. We investigated the mRNA expression profile of the risk alleles HLA-DRB1*15 and HLA-DRB1*13 in a cohort of subjects both multiple sclerosis (MS) patients and healthy controls. Moreover, we explored the expression of the allele HLA-DRB1*11 that is very frequent in our cohort from southern Italy. We found that the expression of MS-associated alleles in heterozygous MS patients was always higher than the nonassociated alleles. The differential risk allele expression occurred also in nonaffected subjects, though with a lower increment compared to MS patients.

Aerodynamic findings and Voice Handicap Index in Parkinson's disease.

OBJECTIVE: To verify possible relations between vocal disability and aerodynamic measures in selected Parkinson's disease (PD) patients with low/moderate-grade dysphonia. METHODS: Fifteen idiopathic dysphonic PD male patients were examined and compared with 15 euphonic subjects. Testing included the following measures: Voice Handicap Index (VHI), maximum phonation time (MPT), mean estimated subglottal pressure (MESGP), mean sound pressure level (MSPL), mean phonatory power (MPP), mean phonatory efficiency (MPE) and mean phonatory resistance (MPR). RESULTS: Statistical analysis showed: a significant reduction in MPR and MSPL in PD subjects compared to the healthy ones; a significant positive correlation between VHI score and MSPL, MPR, MPP, MESGP and a significant negative correlation between VHI and MTP within PD subjects. Test for multiple linear regression showed a significant correlation between VHI score, MPT, MPR and MSPL. CONCLUSIONS: A relationship between VHI and aerodynamic measures was shown in the present study. Compensatory mechanisms may aggravate vocal disability in PD subjects.

No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon ß1b therapy in relapsing-remitting multiple sclerosis (the ARIANNA study).

BACKGROUND: A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis. OBJECTIVES: The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remitting multiple sclerosis. METHODS: This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon ß1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months. RESULTS: A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months. CONCLUSIONS: Our results suggest that the combination of atorvastatin and interferon ß1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis.

Serum uric acid is associated with apathy in early, drug-naïve Parkinson's disease.

Both low serum uric acid (UA) levels and apathy are considered biomarkers of cognitive decline and dementia in Parkinson's disease (PD). There is an urgent need to combine different biomarkers to predict disease course in PD. Data on the relationship between serum UA levels and apathy in PD are lacking. The aim of this study is to evaluate the relationship between serum UA levels and pure apathy in early, drug-naïve PD patients. Forty-nine early, drug-naïve PD patients were enrolled and stratified into two groups using the median serum UA levels at diagnosis (Group 1 serum UA ≤ 4.8 mg/dl; Group 2 serum UA > 4.8 mg/dl). The cohort was followed for the first 2 years of disease. Apathy was evaluated with the Apathy Evaluation Scale (AES). Patients with lower serum UA levels presented significant higher AES score compared to patients with higher serum UA levels. Regression analysis showed that baseline serum UA levels were significant determinants of AES scores at both baseline and 2-year follow up, irrespective of gender, age, attention/executive functions and dopamine replacement therapy when applicable. This is the first study showing a link between serum UA levels and apathy in non-demented, non-depressed, early, drug-naïve PD, being lower serum UA levels associated with greater apathy. Further follow up of our patients and replication of this observation in independent cohorts are needed to establish if this combination of biomarkers may help in characterizing a subgroup of PD patients at diagnosis.

The management of multiple sclerosis by reference centers in south of Italy: a 2011 survey on health demands and needs in Campania region.

This cross-sectional study has investigated the diagnostic and therapeutic management of patients suffering from multiple sclerosis (MS) in the Campania Region (Italy). A survey involving all the reference centers for MS in Campania Region was conducted from March to August 2011. Centers responded to a web-administered questionnaire on management and clinical characteristics of MS patients. In the study period, 3263 patients (mean age 37 years, 66 % females) accessed the centers. Patients received a first diagnosis of MS in 161 cases (4.9 %). About 37 % of the subjects without a previous diagnosis came to the centers on their own initiative. All patients underwent a complete neurological examination and expanded disability status scale. The other most common investigations were magnetic resonance imaging (44.0 %) and evoked potentials (22.1 %). The number of treated patients was 2797 (87.1 %). The most used drugs were interferon ß and glatiramer acetate. The time between diagnosis and initiation of therapy exceeded 6 months in 32 % of cases. Second-line drugs were under-used: 16 % of patients who might benefit from them show high clinical and radiological disease activity despite treatment with immunomodulant drugs. The MS care management of the surveyed centers showed consistent margins for improvement in 2011. Even though these data do not represent the current situation, they can be used to monitor improvements in MS care.

The use of University of Pennsylvania Smell Identification Test in the diagnosis of Parkinson's disease in Italy.

Hyposmia is a common finding in Parkinson's disease (PD). The 40-item University of Pennsylvania Smell Identification Test (UPSIT-40) has been adapted and administered in several countries as a diagnostic tool in the diagnosis of PD. We have developed a culturally adapted version of the UPSIT-40 and applied it to 61 nondemented Italian controls and to 68 PD patients. Multiple linear regression analysis was performed to assess the factors that independently influence UPSIT-40 and logistic regression analysis was employed to study the usefulness of UPSIT-40 to predict PD diagnosis. Multiple linear regression analysis showed that PD diagnosis (p < 0.001), age (p = 0.006), gender (p = 0.003) and smoking status (p = 0.03) were significant independent predictors of the UPSIT-40 total score. Using diagnosis as dependent variable, logistic regression analysis showed that UPSIT-40 total score (p < 0.001) was an independent predictor of PD. Using a score ≤ 21/40 as a cut-off point for assigning subjects to PD group, the UPSIT-40 total score differentiated PD and control subjects with 82 % sensitivity and 88.2 % specificity. The adapted version of UPSIT-40 may be useful in addition to clinical examination to improve accuracy of diagnosis of PD in Italian population.

Renal Cystinuria and Immune Cells (T Lymphocytes) Dysfunction: What We Know about?

INTRODUCTION: Cystinuria (CYS) is the most common monogenic kidney stone disease. METHODS: Starting from an unusual case of CYS associated to primary sclerosing cholangitis, inflammatory bowel disease (IBD), and autoimmune hepatitis in a young male, we carefully review the literature and propose here a working hypothesis regarding the potential risk of cystinuric patients to develop conditions due to immune system dysregulation. To corroborate this hypothesis, we retrospectively evaluate the frequency of dysimmunity in a monocentric cohort including 36 cystinuric patients compared to healthy and disease controls. RESULTS: CYS patients have an increased prevalence of atopic disease compared to disease controls (p = 0.03) and 16.7% of CYS subjects were diagnosed with allergic disease to a variety of antigens. CONCLUSION: Further studies are needed to define the relationship between proximal tubular transport defect of CYS and dysregulated immunity.

Bone mineral density assessment in patients with cystinuria.

BACKGROUND: Cystinuria is a rare genetic disease characterized by impaired tubular transport of cystine. Clinical features of cystinuria mainly include nephrolithiasis and its complications, although cystinuric patients may present with other comorbidities. There are currently no data on bone features of patients with cystinuria. Our aim is to characterize bone mineral density (BMD) in cystinuria. METHODS: Our study included adult cystinuric patients with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 followed at 3 specialized outpatient clinics in Italy (Rome, Naples and Verona). Markers of bone turnover were analyzed in a centralized laboratory. Clinical, biochemical and dual-energy X-ray absorptiometry (DEXA) data were collected from September 2021 to December 2022. Linear regression models were used to evaluate statistically significant deviations from zero of Z-scores. RESULTS: Twenty-seven patients were included in the study. Mean (SD) age was 37 (15) years, 41% were women. Mean estimated glomerular filtration rate was 99 mL/min/1.73 m2. Serum parameters associated with bone turnover (parathyroid hormone, FGF23, calcium and phosphate) were all in the normal range, with only 4 patients showing mild hypophosphatemia. Prevalence of low bone mineral density, defined as Z-score ≤ - 2 at any site, was 15%. Average Z-scores were negative across most sites. CONCLUSIONS: Our study suggests that cystinuric patients have lower bone mineral density compared with individuals of the same sex and age, even when their kidney function is normal.

Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing-remitting active multiple sclerosis patients: a longitudinal controlled trial of combination therapy.

A large body of evidence suggests that, besides their cholesterol-lowering effect, statins exert anti-inflammatory action. Consequently, statins may have therapeutic potential in immune-mediated disorders such as multiple sclerosis. Our objectives were to determine safety, tolerability and efficacy of low-dose atorvastatin plus high-dose interferon beta-1a in multiple sclerosis patients responding poorly to interferon beta-1a alone. Relapsing-remitting multiple sclerosis patients, aged 18-50 years, with contrast-enhanced lesions or relapses while on therapy with interferon beta-1a 44 microg (three times weekly) for 12 months, were randomized to combination therapy (interferon + atorvastatin 20 mg per day; group A) or interferon alone (group B) for 24 months. Patients underwent blood analysis and clinical assessment with the Expanded Disability Status Scale every 3 months, and brain gadolinium-enhanced magnetic resonance imaging at screening, and 12 and 24 months thereafter. Primary outcome measure was contrast-enhanced lesion number. Secondary outcome measures were number of relapses, EDSS variation and safety laboratory data. Forty-five patients were randomized to group A (n = 21) or B (n = 24). At 24 months, group A had significantly fewer contrast-enhanced lesions versus baseline (p = 0.007) and significantly fewer relapses versus the two pre-randomization years (p < 0.001). At survival analysis, the risk for a 1-point EDSS increase was slightly higher in group B than in group A (p = 0.053). Low-dose atorvastatin may be beneficial, as add-on therapy, in poor responders to high-dose interferon beta-1a alone.

miRNA profile is altered in a modified EAE mouse model of multiple sclerosis featuring cortical lesions.

Cortical lesions represent a hallmark of multiple sclerosis and are proposed as a predictor of disease severity. microRNAs are suggested to be important players in the disease pathogenesis and the experimental autoimmune encephalomyelitis animal model. We implemented a mouse model recapitulating more closely the human pathology as it is characterized by both an autoimmune heterogeneity and the presence of cortical lesions, two parameters missing in experimental autoimmune encephalomyelitis. In our model, mice clustered in two groups displaying high or low clinical scores. Upon cortical cytokine injection, lesions appeared with a specific topography while cortical miRNA profiles were altered. These two features differed according to disease severity. We evidenced changes in miRNA regulators and targets suggesting that miRNA alteration had functional repercussions that could explain the differences in cortical lesions. This model represents a crucial tool for the study of both miRNA involvement and cortical lesion formation in disease pathogenesis.

Communication in Multiple Sclerosis: Pragmatic Deficit and its Relation with Cognition and Social Cognition.

OBJECTIVE: Cognitive functions have been largely investigated in multiple sclerosis. Less attention has been paid to social communication abilities, despite their presumptive affect on quality of life. We run the first comprehensive assessment of pragmatic skills in multiple sclerosis, evaluating also the relationship between pragmatics and other cognitive domains. METHODS: Forty-two multiple sclerosis patients and 42 controls were tested for pragmatic abilities, neuro-cognition, social cognition, depression, and fatigue. RESULTS: Patients performed poorly in most pragmatic tasks compared to controls. Globally, 55% of patients performed below the 5th percentile in the total pragmatic score. Notably, pragmatic skills did not differ between cognitively impaired and unimpaired patients. However, an association was found between pragmatics and verbal fluency, as measured in the Word List Generation. Finally, we observed an association of pragmatic abilities with social cognition, and a trend with psychosocial functioning. CONCLUSION: Overall, the study shows a diffuse pragmatic impairment in multiple sclerosis, not associated with the patient's global neuropsychological profile. By contrast, our findings suggest a close relation between pragmatics and specific cognitive aspects such as executive functions, and between pragmatics and social cognition. This study underlines the need of looking beyond classical cognitive performance, to consider underestimated communicative disturbances of high clinical relevance.

Pragmatic abilities in multiple sclerosis: The contribution of the temporo-parietal junction.

Recent studies showed that multiple sclerosis (MS) patients might experience communicative deficits, specifically in pragmatics (i.e., the ability to integrate the context-dependent aspects of language). A crucial region for pragmatics is the temporo-parietal junction, in particular the so-called Geschwind's area (GA), which is involved in high-level language processes, including the comprehension of narratives, metaphor, and irony. We evaluated the relationship between pragmatic abilities, measured through the Assessment of Pragmatic Abilities and Cognitive Substrates (APACS) test, and the functional connectivity (FC) of the bilateral GAs, assessed through a seed-based analysis of Resting-State fMRI in patients with MS. A positive correlation was observed between APACS scores and the FC for both the right and the left GA and the paracingulate cortex. Our findings suggest that the brain FC for social communication involves connections extending over both hemispheres, including right and left GAs and right and left paracingulate cortex, possibly impaired in patients with MS. This study offers preliminary evidence for future researches enrolling also a control sample to explore the involvement of GA in pragmatics in neurological disorders as well as in healthy conditions.

Correlation between fatigue and brain atrophy and lesion load in multiple sclerosis patients independent of disability.

BACKGROUND: Fatigue is a major problem in multiple sclerosis (MS), and its association with MRI features is debated. OBJECTIVE: To study the correlation between fatigue and lesion load, white matter (WM), and grey matter (GM), in MS patients independent of disability. METHODS: We studied 222 relapsing remitting MS patients with low disability (scores or=5; n=197) and low-fatigue groups (FSS

Immunometabolic profiling of T cells from patients with relapsing-remitting multiple sclerosis reveals an impairment in glycolysis and mitochondrial respiration.

BACKGROUND: Metabolic reprogramming is shaped to support specific cell functions since cellular metabolism controls the final outcome of immune response. Multiple sclerosis (MS) is an autoimmune disease resulting from loss of immune tolerance against central nervous system (CNS) myelin. Metabolic alterations of T cells occurring during MS are not yet well understood and their studies could have relevance in the comprehension of the pathogenetic events leading to loss of immune tolerance to self and to develop novel therapeutic strategies aimed at limiting MS progression. METHODS AND RESULTS: In this report, we observed that extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), indicators of glycolysis and oxidative phosphorylation, respectively, were impaired during T cell activation in naïve-to-treatment relapsing remitting (RR)MS patients when compared with healthy controls. These results were also corroborated at biochemical level by a reduced expression of the glycolitic enzymes aldolase, enolase 1, hexokinase I, and by reduction of Krebs cycle enzymes dihydrolipoamide-S-acetyl transferase (DLAT) and dihydrolipoamide-S-succinyl transferase (DLST). Treatment of RRMS patients with interferon beta-1a (IFN beta-1a) was able to restore T cell glycolysis and mitochondrial respiration as well as the amount of the metabolic enzymes to a level comparable to that of healthy controls. These changes associated with an up-regulation of the glucose transporter-1 (GLUT-1), a key element in intracellular transport of glucose. CONCLUSIONS: Our data suggest that T cells from RRMS patients display a reduced engagement of glycolysis and mitochondrial respiration, reversible upon IFN beta-1a treatment, thus suggesting an involvement of an altered metabolism in the pathogenesis of MS.

Levetiracetam for cerebellar tremor in multiple sclerosis: an open-label pilot tolerability and efficacy study.

PURPOSE: Disabling tremor is frequent in multiple sclerosis (MS) and its treatment remains challenging. We conducted an open-label trial to evaluate the effect of levetiracetam (LEV) to treat cerebellar tremor in MS patients. PATIENTS AND METHODS: Fourteen MS patients, aged 27 to 57 years, with cerebellar tremor. Tremor duration ranged from 3 to 14 years. The tremor clinical rating scale, the spiral drawings scale, and ataxia clinical scale were used to assess the severity of tremor. Data about the tremor-induced disability were obtained by using the specific Activities of Daily Living Questionnaire (ADL). LEV was orally administered at a starting dose of 500 mg twice daily for one week followed by increments of 500 mg twice daily each week up to the target dose of 50 mg/Kg/day. Patients were evaluated at baseline and two weeks after the end of titration phase. The Wilcoxon matched-pairs test was used for statistical analysis. RESULTS: Eleven patients completed the trial. LEV administration was associated with subjective and objective improvement of the tremor, with significant lowering of all tremor measurements' sum of scores as well as of ADL mean score between the baseline and follow-up. No correlation was found between the degree of improvement of the tremor and the disease duration or progression. LEV was well tolerated by subjects who completed the study. CONCLUSIONS: LEV could be useful for the management of cerebellar tremor in MS and the good tolerability makes it easy to test. LEV long-term efficacy should be confirmed in extended studies.

Absence of cerebrospinal fluid oligoclonal bands is associated with delayed disability progression in relapsing-remitting MS patients treated with interferon-beta.

To assess the role of CSF oligoclonal bands (OB) in determining the clinical outcome in patients with relapsing-remitting multiple sclerosis (RRMS) treated with IFN-beta, we carried out a retrospective, multicentre, observational study recruiting 209 RRMS patients from six MS centres from northern, central and southern areas of Italy under treatment with IFN-beta-1a i.m., IFN-beta-1a s.c. and IFN-beta-1b s.c. Twenty-two of 209 patients (10.6%) showed no OB in CSF. The patients without had, at disease onset, significantly higher frequency of visual disturbances (p=0.02) and less sensory involvement (p=0.04) than those with OB. A statistical trend (p=0.056) towards a longer time to reach sustained disability progression during treatment was found in patients without compared to those with OB. Thirty-six of 187 (19%) patients with OB worsened by at least 1 EDSS point compared to none of 22 (0%) OB-negative patients (p=0.017). The delaying of disability progression in OB-negative patients during treatment was significantly dependent only on the number of baseline MRI T2-weighted lesions (p=0.012) that was found to be significantly lower in OB-negative than in OB-positive patients (p=0.04). The absence of OB and low number of baseline T2-weighted lesions in this cohort of MS patients are favourable prognostic factors influencing the clinical response to IFN-beta treatment in RRMS patients.

Neuropsychological assessment, quantitative MRI and ApoE gene polymorphisms in a series of MS patients treated with IFN beta-1b.

Few trials issued the effect of disease-modifying medications on cognitive functions in multiple sclerosis. We designed an open-label longitudinal study to evaluate, during 2 years, cognitive performance and its relationship with MRI data and ApoE polymorphism findings in a group of relapsing-remitting (RR) multiple sclerosis (MS) Interferon (IFN) beta-1b-treated patients (median age 30 years, median disease duration 3.4 years). Complete neuropsychological battery was grouped into attention, information learning/memory, language and visuo-spatial functions. Fifty-two patients (33 females) were enrolled in the study. Six patients (11.5%) dropped out, mainly due to side effects. At baseline neuropsychological evaluation, we found 54% normal, 42% mildly impaired and 4% moderately impaired patients. At 2 years follow-up, cognitive status was stable in 65%, improved in 33% and worsened in 2% of patients. No significant relations were found between global cognitive outcome vs. EDSS change, clinical disease activity, MRI data or ApoE gene polymorphisms over the 2 years follow-up. EDSS and MRI fractional volumes were found to correlate with the performance at single tests. Twenty-one patients (45.6%) showed active MRI scans throughout the study, without any worsening at the corresponding neuropsychological examination. This ongoing trial suggests a possible beneficial effect of IFN beta-1b treatment on cognitive functions in RRMS patients. Extension of follow-up and further data analyses are needed to confirm and clarify these findings.

Microalbuminuria predicts the recurrence of cardiovascular events in patients with essential hypertension.

OBJECTIVES: Microalbuminuria (MAU) is associated with an enhanced risk of cardiovascular events. The prevalence of MAU and its prognostic impact has an important role in the stratification of cardiovascular risk in patients with essential hypertension. This is an observational, prospective study performed by 13 general practitioners aiming at assessing the prevalence and prognostic relevance of MAU in essential hypertension. METHODS: Patients with essential hypertension and with recent determination of MAU were enrolled into the study by general practitioners, and were followed up for 3 years. Primary end point was the occurrence of major cardiovascular events during the follow-up. RESULTS: Out of 1024 unselected patients, consecutively enrolled from January 2009 to March 2010, 804 completed the 3-year follow-up. Patients were categorized into two groups according to the absence (n = 523, 65%) or presence (n = 281, 35%) of MAU. During the follow-up, 41 cardiovascular events (1.69 events/100 patient-years) were reported. The presence of MAU was not associated with increased risk of cardiovascular events (adjusted hazard ratio = 1.32; 95% confidence interval 0.290-4.340, P = 0.097). When the analysis was restricted to the patients with previous cardiovascular event, MAU (adjusted hazard ratio = 2.18; 95% confidence interval 0.42-2.43, P = 0.031), together with age, metabolic syndrome, diabetes, and smoking, independently predicted the occurrence of cardiovascular events. CONCLUSION: Presence of MAU in patients with essential hypertension is not associated with increased risks of cardiovascular events. At the variance, in patients with previous cardiovascular events, MAU was found to predict recurrent events. Thus, the assessment of MAU could be considered a useful tool in secondary prevention.

The effects of mechanical focal vibration on walking impairment in multiple sclerosis patients: A randomized, double-blinded vs placebo study.

BACKGROUND: Multiple Sclerosis is a heterogeneous disorders involving in early stage gait and balance. Together with immunomodulating therapies, rehabilitation had a crucial role in improving motor tasks and quality of life. Between the emerging techniques, Focal Vibrations (FV) could play a role, but they have been used in MS only to reduce muscle tone and fatigue alone or together with botulinum toxin. OBJECTIVE: To assess whether FV is effective on walking impairment in a cohort of MS patients. METHODS: We performed a single-centre randomized, double-blind, sham-controlled study to investigate efficacy of FV vs sham vibration in 20 RR MS patients. Ten patients received treatment with the active device and ten patients sham treatment. Demographical, clinical and gait instrumental data analysis have been collected for each patient at baseline (T0), after treatment (T1) and after three weeks of wash out (T2). RESULTS: Both groups were clinically and demographically comparable. Treated patients showed significant improvements during the first right step (FRS) (p = 0.007), average stride lenght (ASL) (p = 0.012), double support right (DSRT) (p = 0.016) and left (DSLT) (p = 0.003) time. Non-treated patients didn't show any significance for any dynamic variables. Moreover, on posturographic measurements we registered only a trend towards significance in swing area with eyes open (SAEO) (p = 0.087). We also found in treated group significant improvements in FRT (p = 0.018); BBS (p = 0.037) and FSS scales (p = 0.038) between T1 and T0. Lastly, we found a significant inverse correlation in the treated group between disease duration and percentage of improvement for DSLT (r = - 0.775; p = 0.014) in T1 vs T0 and percentage of improvement of FSS, with an inverse correlation with both disease duration (r = - 0.775; p = 0.014) and AGE (r = - 0.733, p = 0.025) in T1 vs T0CONCLUSION: Our results suggest a beneficial effect of FV on walking impairment in MS patients suffering from spasticity and/or postural instability, which partially lasted until follow up.

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-ß1a and Circulating Proinflammatory Cytokines in Relapsing-Remitting Multiple Sclerosis.

Palmitoylethanolamide (PEA) is an endogenous lipid mediator known to reduce pain and inflammation. However, only limited clinical studies have evaluated the effects of PEA in neuroinflammatory and neurodegenerative diseases. Multiple sclerosis (MS) is a chronic autoimmune and inflammatory disease of the central nervous system. Although subcutaneous administration of interferon (IFN)-ß1a is approved as first-line therapy for the treatment of relapsing-remitting MS (RR-MS), its commonly reported adverse events (AEs) such as pain, myalgia, and erythema at the injection site, deeply affect the quality of life (QoL) of patients with MS. In this randomized, double-blind, placebo-controlled study, we tested the effect of ultramicronized PEA (um-PEA) added to IFN-ß1a in the treatment of clinically defined RR-MS. The primary objectives were to estimate whether, with um-PEA treatment, patients with MS perceived an improvement in pain and a decrease of the erythema width at the IFN-ß1a injection site in addition to an improvement in their QoL. The secondary objectives were to evaluate the effects of um-PEA on circulating interferon-γ, tumor necrosis factor-α, and interleukin-17 serum levels, N-acylethanolamine plasma levels, Expanded Disability Status Scale (EDSS) progression, and safety and tolerability after 1 year of treatment. Patients with MS receiving um-PEA perceived an improvement in pain sensation without a reduction of the erythema at the injection site. A significant improvement in QoL was observed. No significant difference was reported in EDSS score, and um-PEA was well tolerated. We found a significant increase of palmitoylethanolamide, anandamide and oleoylethanolamide plasma levels, and a significant reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile compared with the placebo group. Our results suggest that um-PEA may be considered as an appropriate add-on therapy for the treatment of IFN-ß1a-related adverse effects in RR-MS.