Influence of Interferon beta treatment on quality of life in multiple sclerosis patients

BACKGROUND: Interferon-beta (IFN-β) shows beneficial effect on the course of multiple sclerosis (MS), nevertheless its route and frequency of administration and side effects might impact negatively the quality of life (QoL) of MS patients. The objective of this study was to evaluate the influence of IFN-β on QoL in MS patients. METHODS: Seventy-seven disease modifying treatment (DMT) free and 41 IFN-β treated MS patients were evaluated. QoL, assessed by MSQoL-54, was related to IFN-β treatment and to clinical and demographic parameters at baseline and after two years. Multivariate hierarchical linear model for repeated measurements was used. RESULTS: Treated patients showed a younger age, a lower disease duration and a higher relapse rate in the two years preceding study entry. At inclusion time treated and untreated patients did not differ in relapse rate, expanded disability status scale (EDSS), fatigue, depression, physical and mental QoL. IFN-β did not influence QoL at inclusion time, but when QoL was evaluated after two years, treatment negatively affected mental QoL. Depression and fatigue negatively influenced physical and mental QoL both at baseline and after two years. EDSS correlated with a poor physical QoL only at baseline. CONCLUSION: IFN-β had a negative impact on QoL over the time in MS patients, influencing mainly mental QoL. The impairment of QoL in MS was strongly associated with increasing fatigue and depression, whereas clinical disability had a minor unfavourable role

Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis

The DNA glycosylase gene MBD4 safeguards genomic stability at CpG sites and is frequently mutated at coding poly-A tracks in mismatch repair (MMR)-defective colorectal tumors (CRC). Mbd4 biallelic inactivation in mice provided conflicting results as to its role in tumorigenesis. Thus, it is unclear whether MBD4 alterations are only secondary to MMR defects without functional consequences or can contribute to the mutator phenotype. We investigated MBD4 variants in a large series of hereditary/familial and sporadic CRC cases. Whereas MBD4 frameshifts were only detected in tumors, missense variants were found in both normal and tumor DNA. In CRC with double-MBD4/MMR and single-MBD4 variants, transition mutation frequency was increased, indicating that MBD4 defects may affect the mutational landscape independently of MMR defect. Mbd4-deficient mice showed reduced survival when combined with Mlh1−/− genotype. Taken together, these data suggest that MBD4 inactivation may contribute to tumorigenesis, acting as a modifier of MMR-deficient cancer phenotype

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p < 0.001), RR = 2.19 for ICU admission (p < 0.001), and RR = 2.43 for death (p < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Survival analysis in families affected by hereditary non-polyposis colorectal cancer

Previous survival studies suggested a better prognosis of hereditary nonpolyposis colorectal cancer (HNPCC) patients compared with the sporadic counterpart. In the present study we evaluated the clinical outcome of HNPCC patients with respect to that of patients with colorectal cancer recorded in a population-based cancer registry. We assessed survival of 85 colorectal cancer patients from 24 unrelated families defined as having HNPCC according to the criteria of the International Collaborative Group, for whom adequate information on subject- and tumor-related parameters and a 5-year follow-up (cancer diagnosis from 1980-1989) were available. Three hundred and seventy- seven colorectal cancer patients, registered from 1984-1986, with a 5-year follow-up, were used for comparison. Colorectal cancer-specific 5-year survival rates were 55.2% and 42.5% for HNPCC and non-HNPCC, respectively. Using Cox regression analysis, tumor staging and location were independently associated with survival, whereas HNPCC diagnosis was not. Stage II HNPCC cases exhibited a better prognosis than non-HNPCC patients. By Cox regression analysis, none of the variables were significantly related to survival. Both overall and stage II HNPCC cases showed a survival advantage in comparison with non-HNPCC patients. However, the difference disappeared when clinical and pathological variables were controlled for with a Cox regression analysis

Mutations of the 'minor' mismatch repair gene MSH6 in typical and atypical hereditary nonpolyposis colorectal cancer

Mutations of the mismatch repair (MMR) genes MLH1 and MSH2 are associated with hereditary nonpolyposis colorectal cancer (HNPCC), a highly penetrant autosomal dominant condition characterized by hypermutability of short tandemly repeated sequences in tumor DNA. Mutations of another MMR gene, MSH6, seem to be less common than MLH1 and MSH2 defects, and have been mostly observed in atypical HNPCC families, characterized by a weaker tumor family history, higher age at disease onset, and low degrees of microsatellite instability (MSI), predominantly involving mononucleotide runs. We have investigated the MSH6 gene sequence in the peripheral blood of 4 HNPCC and 20 atypical HNPCC probands. Two frameshift mutations within exon 4 were detected in 2 patients. One mutation was found in a proband from a typical HNPCC family, who had developed a colorectal cancer (CRC), a gastric cancer and a rectal adenoma. The CRC and the adenoma showed mild MSI limited to mononucleotide tracts, while the gastric carcinoma was microsatellite stable. The other mutation was detected in an atypical HNPCC proband, whose CRC showed widespread MSI involving both mono- and dinucleotide repeats. The phenotypic variability associated with MSH6 constitutional mutations represents a complicating factor for the optimization of strategies aimed at identifying candidates to MSH6 genetic testing

Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer

Mismatch repair genes MSH2 and MLH1 are considered to be the two major genes that are responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Germline heterozygous inactivating mutations of MSH2 and MLH1 have been identified previously in a substantial fraction of individuals who are predisposed genetically to colorectal carcinoma (CRC) and other tumors of the HNPCC spectrum. With the aim of determining the relevance of these two genes in the Italian population, we submitted to mutational analysis a set of 17 HNPCC families, all of which fulfilled the 'Amsterdam criteria.' A combination of different techniques, including reverse transcription- polymerase chain reaction (RT-PCR) of long fragments and single-strand conformation polymorphism (SSCP) on cDNA and genomic DNA, allowed the identification of ten molecular variants, seven of which are predicted to inactivate mismatch repair function. The mutated predisposing gene was MSH2 in two families and MLH1 in five other families. All of the mutations were characterized by DNA sequencing and appeared to involve different molecular mechanisms, such as short in-frame and out-of-frame deletions, splicing errors, and nonsense mutations. This study also demonstrates that, in the Italian population, a considerable fraction of HNPCC families (at least 41%) is linked to MSH2 and MLH1 mutations