Recent evidence has shown that CD56(bright) NK cells, a subset of NK cells abundant in lymph nodes, may have an immunoregulatory function. In multiple sclerosis (MS), expansion of CD56(bright) NK ...cells has been associated to successful response to different treatments and to remission of disease during pregnancy; how whether they exert immunoregulation in physiologic conditions and whether this is impaired in MS is not known. We dissected the immunoregulatory role of CD56(bright) NK cells function in healthy subjects (HS) and compared it with that of untreated MS subjects or patients with clinically isolated syndrome suggestive of MS (CIS). We found that CD56(bright) NK cells from HS acquire, upon inflammatory cues, the capability of suppressing autologous CD4+T cell proliferation through direct cytotoxicity requiring engagement of natural cytotoxicity receptors (NCRs) and secretion of granzyme B. CD56(bright) NK cells from patients with MS/CIS did not differ in frequency and share a similar phenotype but displayed a significantly lower ability to inhibit autologous T cell proliferation. This impairment was not related to deficient expression of NCRs or granzyme B by CD56(bright) NK cells, but to increased HLA-E expression on T cells from MS/CIS subjects, which could enhance the inhibitory effect mediated by NKG2A that is homogeneously expressed on CD56(bright) NK cells. The defect in controlling autologous T cells by CD56(bright) NK cells in MS/CIS might contribute to the excess of autoimmune response that is associated to disease development.
To assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS), with a specific focus on spontaneous abortion (SA) and congenital anomalies (CA).
Data of all ...pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents. Rates of SA and CA were also compared with those reported in the Italian population. Multivariable logistic and linear regression models were performed.
A total of 92 pregnancies were tracked in 83 women. In the multivariable analysis, natalizumab exposure was associated with SA (odds ratio OR 3.9, 95% confidence interval CI 1.9-8.5,
< 0.001). However, the rate of SA (17.4%) was within the estimates for the general population, as well as the rate of major CA (3.7%). Moreover, exposure to natalizumab and interferon-β (IFN-β) was associated with lower length and weight of the babies (
< 0.001).
Our results showed that natalizumab exposure to up 12 weeks of gestation is associated with an increased risk of SA, although within the limits expected in the general population, whereas the risk of CA needs further investigation. Taking into account the high risk of disease reactivation after natalizumab suspension, pregnancy could be planned continuing natalizumab while strictly monitoring conception.
This study provides Class III evidence that in women with MS, natalizumab exposure increases the risk of spontaneous abortion as compared to IFN-β-exposed or untreated patients (OR 3.9, 95% CI 1.9-8.5).
Prognostic markers of primary progressive multiple sclerosis evolution are needed. We investigated the added value of magnetic resonance imaging measures of brain and cervical cord damage in ...predicting long-term clinical worsening of primary progressive multiple sclerosis compared to simple clinical assessment. In 54 patients, conventional and diffusion tensor brain scans and cervical cord T1-weighted scans were acquired at baseline and after 15 months. Clinical evaluation was performed after 5 and 15 years in 49 patients. Lesion load, brain and cord atrophy, mean diffusivity and fractional anisotropy values from the brain normal-appearing white matter and grey matter were obtained. Using linear regression models, we screened the clinical and imaging variables as independent predictors of 15-year disability change (measured on the expanded disability status scale). At 15 years, 90% of the patients had disability progression. Integrating clinical and imaging variables at 15 months predicted disability changes at 15 years better than clinical factors at 5 years (R2 = 61% versus R2 = 57%). The model predicted long-term disability change with a precision within one point in 38 of 49 patients (77.6%). Integration of clinical and imaging measures allows identification of primary progressive multiple sclerosis patients at risk of long-term disease progression 4 years earlier than when using clinical assessment alone.
To assess the risk of disease reactivation during pregnancy after natalizumab suspension in women with multiple sclerosis (MS).
Data of all pregnancies occurring between 2009 and 2015 in patients ...with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents through a 2-factor repeated measures analysis. Predictors of disease activity were assessed through stepwise multivariable logistic regression models.
A total of 92 pregnancies were tracked in 83 women receiving natalizumab. Among these pregnancies, 74 in 70 women resulted in live births, with a postpartum follow-up of at least 1 year, and were compared with 350 previously published pregnancies. Relapse rate during and after pregnancy was higher in women treated with natalizumab (
< 0.001). In multivariable analysis, longer natalizumab washout period was the only predictor of relapse occurrence during pregnancy (
= 0.001). Relapses in the postpartum year were related to relapses during pregnancy (
= 0.019) and early reintroduction of disease-modifying drugs (DMD;
= 0.021). Disability progression occurred in 16.2% of patients and was reduced by early reintroduction of DMD (
= 0.024).
Taken as a whole, our findings indicate that the combination of avoiding natalizumab washout and the early resumption of DMD after delivery could be the best option in the perspective of maternal risk. This approach must take into account possible fetal risks that need to be discussed with the mother and require further investigation.
This study provides Class IV evidence that in women with MS, the risk of relapses during pregnancy is higher in those who had been using natalizumab as compared to those who had been using interferon-β or no treatment.
Patients with solid or hematological tumors or neurological and immune-inflammatory disorders are potentially fragile subjects at increased risk of experiencing severe coronavirus disease 2019 and an ...inadequate response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination.
We designed a prospective Italian multicenter study to assess humoral and T-cell responses to SARS-CoV-2 vaccination in patients (n = 378) with solid tumors (ST), hematological malignancies (HM), neurological disorders (ND), and immunorheumatological diseases (ID). A group of healthy controls was also included. We analyzed the immunogenicity of the primary vaccination schedule and booster dose.
The overall seroconversion rate in patients after 2 doses was 62.1%. Significantly lower rates were observed in HM (52.4%) and ID (51.9%) than in ST (95.6%) and ND (70.7%); a lower median antibody level was detected in HM and ID versus ST and ND (P < .0001). Similar rates of patients with a positive SARS-CoV-2 T-cell response were found in all disease groups, with a higher level observed in ND. The booster dose improved the humoral response in all disease groups, although to a lesser extent in HM patients, whereas the T-cell response increased similarly in all groups. In the multivariable logistic model, independent predictors of seroconversion were disease subgroup, treatment type, and age. Ongoing treatment known to affect the immune system was associated with the worst humoral response to vaccination (P < .0001) but had no effect on T-cell responses.
Immunosuppressive treatment more than disease type per se is a risk factor for a low humoral response after vaccination. The booster dose can improve both humoral and T-cell responses.
Objectives
We compared the clinical, laboratory, and radiological features of different subgroups of acute transverse myelitis (ATM) diagnosed according to the criteria established by the Transverse ...Myelitis Consortium Working Group (TMCWG) as well as of non-inflammatory acute transverse myelopathies (NIATM) to identify possible short- and long-term prognostic factors.
Methods
A multicenter and retrospective study comprising 110 patients with ATM and 15 NIATM admitted to five Italian neurological units between January 2010 and December 2014 was carried out.
Results
A significantly higher frequency of isolated sensory disturbances at onset in ATM than in NIATM patients (chi-square = 14. 7;
P
= 0.005) and a significantly higher frequency of motor symptoms in NIATM than ATM (chi-square = 12.4;
P
= 0.014) was found. ATM patients with high disability at discharge had more motor-sensory symptoms without (OR = 3.87;
P
= 0.04) and with sphincter dysfunction at onset (OR = 7.4;
P
= 0.0009) compared to those with low disability. Higher age (OR = 1.08;
P
= 0.001) and motor-sensory-sphincter involvement at onset (OR = 9.52;
P
= 0.002) were significantly associated with a high disability score at discharge and after a median 1-year follow-up.
Conclusions
The diagnosis of ATM may prevail respect to that of NIATM when a sensory symptomatology at onset occurs. In ATM, patients older and with motor-sensory involvement with or without sphincter impairment at admission could experience a major risk of poor prognosis both at discharge and at longer time requiring a timely and more appropriate treatment.
Background
COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data ...about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce.
Objective
To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS.
Methods
We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60 days prior to and after the third booster dose.
Results
In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60 days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60 days prior to vaccination, which was 1.9%.
Conclusions
The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS.
Defining immune mechanisms leading to multiple sclerosis (MS) is difficult, due to the great inter-individual difference in immune system responses. The anti-CD52 antibody alemtuzumab transiently ...abolishes differences in immune parameters among individuals, allowing analysis of subsequent immune cell repopulation patterns, and their possible role in MS.
To evaluate the correlation between innate and adaptive immune cell subsets and disease activity in MS in the context of treatment with alemtuzumab.
A two-center observational cohort of patients treated with alemtuzumab underwent immune profiling of T, B, and natural killer (NK) cells, biomarker, clinical and radiological follow-up.
After treatment, the percentage of NK and B cells increased; NK, T- and B-cell populations underwent a profound rearrangement. Within the effector T-cell compartment, treatment led to a transient decrease, followed by an increase, of T-helper 1 cells, and to a transient decrease of T-helper 17 cells. Within the T-regulatory compartment, naïve T-regulatory cells increased. Within the B-cell compartment, memory B cells and mature B cells decreased, whereas transitional B cells increased. Within the NK cell compartment, CD56
NK cells increased. Subjects without disease activity had a greater decrease in serum NfL and greater NK cell/CD3+ T cell ratio. NK cell numbers at baseline and after treatment influenced reconstitution of T and B cells, being inversely correlated with the reconstitution of proinflammatory CD3+ T cells and mature B cells, and directly correlated to the increase in transitional B cells.
The results of this study provide novel evidence that NK cells influence reconstitution of adaptive immune cells upon alemtuzumab and that patients with a successful response to alemtuzumab have an early immune reconstitution dominated by NK cells.
To assess whether the presence of concomitant diseases at multiple sclerosis (MS) diagnosis is associated with the choice and the treatment persistence in an Italian MS cohort.
We included newly ...diagnosed patients (2010-2016) followed in 20 MS centers and collected demographic and clinical data. We evaluated baseline factors related to the presence of comorbidities and the association between comorbidities and the clinical course of MS and the time to the first treatment switch.
The study cohort included 2,076 patients. Data on comorbidities were available for 1,877/2,076 patients (90.4%). A total of 449/1,877 (23.9%) patients had at least 1 comorbidity at MS diagnosis. Age at diagnosis (odds ratio 1.05, 95% confidence interval CI 1.04-1.06;
< 0.001) was the only baseline factor independently related to the presence of comorbidities. Comorbidities were not significantly associated with the choice of the first disease-modifying treatment, but were significantly associated with higher risk to switch from the first treatment due to intolerance (hazard ratio 1.42, CI 1.07-1.87;
= 0.014). Association of comorbidities with risk of switching for intolerance was significantly heterogeneous among treatments (interferon β, glatiramer acetate, natalizumab, or fingolimod; interaction test,
= 0.04).
Comorbidities at diagnosis should be taken into account at the first treatment choice because they are associated with lower persistence on treatment.
PDF
