Background

In the randomized, double-blind, placebo-controlled, phase 3 PREVENT trial (NCT01892345), eculizumab was well tolerated and significantly reduced relapse risk vs placebo in patients with aquaporin-4 immunoglobulin G-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). The treatment effect observed in a prespecified subgroup of patients who received eculizumab monotherapy vs placebo alone (i.e. without concomitant immunosuppressive therapy [IST]) was consistent with the overall population.

Objectives

To examine the long-term efficacy and safety of eculizumab monotherapy in patients with AQP4+ NMOSD during PREVENT and/or its ongoing open-label extension (OLE; NCT02003144).

Methods

During PREVENT and its OLE, adults with AQP4+ NMOSD received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (PREVENT only) with/without concomitant IST. Relapses, hospitalizations, IST changes and adverse events (AEs) with eculizumab monotherapy (PREVENT and its OLE; interim data cut-off, July 31, 2019) or with placebo alone (PREVENT) were descriptively analyzed post hoc.

Results

During PREVENT and/or its OLE, 33 patients received eculizumab monotherapy for a total of 85.3 patient-years (PY). Adjudicated relapses occurred in 1/33 patients (annualized relapse rate [ARR], 0.012; 95% confidence interval [CI]: 0.002–0.082), vs 7/13 with placebo alone in PREVENT. At 192 weeks, 96.2% of patients who received eculizumab monotherapy were relapse-free (95% CI: 0.757–0.994) vs 93.8% of patients who received eculizumab with concomitant IST (95% CI: 0.867–0.972). No patients receiving eculizumab monotherapy required hospitalization for a relapse and none started an IST. The treatment-related AE rate with eculizumab monotherapy in PREVENT and its OLE was similar to that with placebo alone in PREVENT (181.0 and 186.0 events/100 PY, respectively), the infection rate was similar between these groups (174.1 vs 186.0 events/100 PY), and the treatment-related serious AE rate was lower with eculizumab monotherapy than with placebo alone (5.7 vs 23.3 events/100 PY). No meningococcal infections or deaths occurred among these patients.

Conclusions

A very high proportion of patients who had experienced 1–2 relapses in the pre-study year remained relapse-free through 192 weeks of eculizumab monotherapy. Long-term eculizumab monotherapy was well tolerated. These data support the long-term effectiveness of eculizumab monotherapy in reducing relapse risk in AQP4+ NMOSD.

Background

In PREVENT, eculizumab was associated with a significant reduction in relapse risk versus placebo and was well tolerated. In total, 46 patients (26/96 in the eculizumab arm, 20/47 in the placebo arm) were previously treated with the monoclonal antibody rituximab.

Objectives

To describe the efficacy and safety of eculizumab in patients in the PREVENT trial (NCT01892345) who had previously received rituximab.

Methods

Adults with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo with/without concomitant immunosuppressive treatment (except rituximab/mitoxantrone). A post hoc descriptive analysis was performed using data from patients with any prior rituximab treatment (within the previous year only for review of adverse events [AEs]) recorded more than 3 months before randomization.

Results

Baseline characteristics of the prior-rituximab subgroup were similar to those of the total PREVENT population; however, the subgroup included a lower proportion of Asian patients (10.9% vs 36.4% in total PREVENT) and greater representation from the Americas (58.7% vs 30.8%). In the subgroup, median times from last dose of rituximab to meningococcal vaccination and to first dose of study treatment were 31.7 and 38.7 weeks, respectively. Adjudicated relapses occurred in 1/26 patients (3.8%) and 7/20 patients (35.0%) in the eculizumab and placebo arms (hazard ratio: 0.093; 95% confidence interval: 0.011–0.755; p = 0.0055), respectively. Rates of AEs for eculizumab and placebo were 1025.8 and 1029.1 events/100 patient-years (100% of patients), respectively, and rates of serious AEs were 46.9 and 66.0 events/100 patient-years (38.9% and 47.1% of patients), respectively. Serious infections/infestations were recorded in 2/18 patients (11.1%) and 2/17 patients (11.8%) in the eculizumab and placebo arms, respectively.

Conclusions

In patients in PREVENT who had previously received rituximab, the risk of adjudicated relapse was significantly lower with eculizumab than with placebo. Rates of serious infections were similarly low with eculizumab and placebo.

Background

Historically, disease activity diminished during pregnancy in women with relapsing-remitting MS. Today, women with high disease activity are more likely to attempt pregnancy due to the disease control that new therapies offer. But disease activity during pregnancy in the modern day remains understudied.

Objectives

Describe disease activity in a modern pregnancy cohort, grouped by preconception disease-modifying therapy (DMT) class; determine the predictors of relapse during pregnancy.

Methods

Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 were included. DMT were classed by low, moderate and high-efficacy. Annualized relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of relapse during pregnancy were determined using clustered logistic regression.

Results

We included 1640 pregnancies from 1452 women. DMT used in the year before conception were none (n=346), low (n=845), moderate (n=207) and high-efficacy (n=242). Most common DMT in each class was interferon-beta (n=597), fingolimod (n=147) and natalizumab (n=219) for low, moderate and high-efficacy respectively. Conception EDSS ≥2 was more common in higher efficacy DMT groups (high: 41.3%; moderate 28.5%; low 22.4%; none 20.2%). For low-efficacy and no DMT groups, ARR fell through pregnancy. ARR of the moderate-efficacy group increased in the 1^st pregnancy trimester (0.55 [95% CI 0.36-0.80] vs 0.14 [95% CI 0.10-0.21] on low-efficacy), then decreased to a trough in the third. Conversely, ARR steadily increased throughout pregnancy for those on high-efficacy DMT (3^rd trimester: 0.42 [95% CI 0.25-0.66] vs 0.12 [95% CI 0.07-0.19] on low-efficacy). Higher efficacy DMT groups were associated with higher ARR in the early postpartum period (high: 0.84 [95% CI 0.62-1.1]; moderate: 0.90 [95% CI 0.65-1.2]; low: 0.47 [95% CI 0.38-0.58]). Preconception use of high and moderate-efficacy DMT and higher preconception ARR were predictors of relapse in pregnancy. But, continuation of high-efficacy DMT into pregnancy was protective against relapse (odds ratio 0.80 [95% CI 0.68-0.94]). Age ≥35 years was associated with reduced odds of relapse.

Conclusions

Women with RRMS treated with moderate or high-efficacy DMT are at greater risk of relapse during pregnancy. Careful pregnancy management, and use of long-acting high-efficacy DMT preconception, or continuing natalizumab into pregnancy, may prevent relapse in pregnancy.

Background

The emergence of a new coronavirus (COVID-19) and the subsequent pandemic present a unique challenge to neurologists managing patients with multiple sclerosis (MS). Preliminary reports do not support an increased risk of severe outcome associated with disease modifying therapies (DMTs) but real-world evidence is lacking.

Objectives

To describe our experience in 14 patients with MS who have been affected by SARS-CoV-2 (with a clinical, RT-PCR, or serological diagnosis) and who were being treated with cladribine in Spain.

Methods

We conducted a consecutive clinical series study including cases occurred in Spain since January 31, 2020 when the first COVID-19 patient was detected in Spain until the end of June 2020.

Results

Patients were mostly female (64%), with an average age of 40.1 (± 12.0) years and a disease duration of 9.7 (± 8.9) years. Median EDSS was 1 (IQR 0–2.5), and the average time on treatment with cladribine was 7.7 (±5.77) months. Two patients had grade 1 lymphopenia, five patients had grade 2 lymphopenia, one patient had grade 3 lymphopenia and six patients were in normal range. Only 1 patient required hospitalization. None required ICU care, or intubation. 93% of the patients improved without any specific treatment. 2 patients (14%) were asymptomatic, 11 (79%) were mild and 1 (7%) was moderate. All recovered without sequelae. 7 of the patients (50%) had a serology test done that showed presence of anti-viral antibodies of IgG and IgM type in all cases.

In our series the patients had a favorable evolution, and all recovered. Factors that could have influenced those results could be the age of the patients, the lack of other risk factors and the mechanism of action of cladribine. It is known that the limited activity of cladribine on cells of the innate immune system and its relatively minor impact on CD8 T cells and plasma cells may have implications for maintained protection from bacterial and viral infections. Importantly, cladribine CD4+ T cell and B cells depletion is partial and transient. The short-term dosing regimen of oral cladribine, potentially reduces depleting effects on the innate immune system.

Conclusions

From this limited number of patients our observations suggest that cladribine treatment does not appear to worsen COVID-19 disease prognosis. MS is a debilitating disease and discontinuing effective treatments might have adverse consequences, benefit/risk assessment is crucial in the current context. Our patients treated with cladribine had an adequate resolution of COVID-19 and mounted an immune response, however more studies are necessary to confirm and extend our preliminary findings.

Background

Infections are an important cause of hospitalization in patients with MS. Data on outcomes of COVID-19 in patients with MS are limited

Objectives

To quantify the risks of infection, hospitalization, admission to intensive care and death due to SARS-CoV-2 infection among patients with MS relative to the general population, and to identify factors associated with risk of hospitalization

Methods

A regional registry was created to collect data on incidence, hospitalization rates, intensive care unit (ICU) admission and death in patients with MS and COVID-19. National government outcomes and seroprevalence data were used for comparison.

Results

Two-hundred nineteen patients with MS were included in the registry, 51 of whom were hospitalized. The infection incidence rate (IR) was lower in patients with MS than the general population (adjusted IR ratio 0.78; 95% confidence interval: 0.70–0.80), but hospitalization rates were higher (adjusted relative risk 6.52 [6.13–7.04]). Disease severity was generally low, with only one ICU admission and five deaths. Males with MS had higher incidence rates and risk of hospitalization than females. No association was found between the use of any disease-modifying therapy (DMT) and hospitalization risk.

Conclusions

Patients with MS do not appear to have greater risks of SARS-CoV-2 infection or severe COVID-19 outcomes compared with the general population. The decision to start or continue DMT should be based on a careful risk-benefit assessment.

Background

Patients with relapsing-remitting multiple sclerosis (RRMS) often experience disease activity despite receiving a disease-modifying therapy (DMT). The Phase IIIb CASTING study (NCT02861014) of ocrelizumab evaluated the efficacy/safety in patients with RRMS who had a prior suboptimal response to one or two DMTs (primary endpoint: 2-year no evidence of disease activity [NEDA] rate).

Objectives

To evaluate CASTING 2-year NEDA outcomes by inclusion criteria, baseline characteristics and prior DMT.

Methods

Patients (Expanded Disability Status Scale [EDSS] score ≤4.0; discontinued prior DMT of ≥6 months’ duration due to suboptimal disease control) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. The primary endpoint of NEDA (with prespecified MRI re-baselining at Week 8) was defined as absence of: protocol-defined relapses, 24-week confirmed disability progression, T1‑weighted contrast-enhancing and new/enlarging T2-weighted lesions over 2 years.

Results

A total of 680 patients were evaluated (female, 64%; mean [SD] baseline EDSS score, 2.1 [1.1]; pretreated with one or two DMTs, including orals and injectables, n=411 [60.4%]/n=269 [39.6%]; enrolled due to activity of: MRI only, n=167 [24.6%]; relapse only, n=238 [35.0%]; MRI and relapse, n=275 [40.4%]). After 2 years, 74.8% (n/N=492/658) of patients had NEDA (with MRI re-baselined at Week 8). The NEDA rate was highest among patients enrolled due to MRI activity alone (80.6%) versus enrollment for relapse (75.1%) or relapse with MRI (70.5%). NEDA rates across disease-related subgroups were highest in the subgroups of baseline EDSS score <2.5 (77.2%), ≤1 relapse prior to enrollment (78.2%) and the event leading to enrollment occurring ≥6 months prior to study entry (75.8%) versus the counterpart subgroups of EDSS score ≥2.5 (70.8%), >1 relapse prior to enrollment (66.3%) and the event leading to enrollment occurring <6 months prior to entry (71.0%). The NEDA rate did not vary by baseline age (≤40 years, 74.7%; >40 years, 75.0%). NEDA rates were higher in patients receiving one prior DMT (77.6%) versus two prior DMTs (70.3%) and remained generally high when stratified by the last prior DMT received before enrollment: interferons, 81.1%; glatiramer acetate, 73.9%; dimethyl fumarate, 73.8%; teriflunomide 69.8%; fingolimod, 68.9%.

Conclusions

The NEDA rate was high overall and across a wide range of disease-related and demographic subgroups, regardless of prior treatment background.

Background

Teriflunomide, is an approved treatment for relapsing-remitting multiple sclerosis (RRMS) . The mechanism of action is not fully elucidated yet.

Objectives

The main goal of this study was to identify the changes in blood immune cells in clinical practice that can predict a better response to treatment.

Methods

RRMS patients who initiated teriflunomide treatment were included in the study. We studied peripheral blood cells obtained before and 6 months after treatment initiation.

Patients were classified in two groups: no evidence of disease activity (NEDA) or ongoing disease activity (ODA) after a year of follow-up.

Wilcoxon matched pair tests were used to assess differences between basal and 6 months after treatment results. Correlations were assessed by Mann–Whitney test. P-values below 0.05 were considered as significant.

Results

A total of 51 RRMS patients (31 females and 20 males) were included in this study. The mean age at the start of teriflunomide was 41 years. Baseline EDSS was 1.80. 18 patients were treatment naive, 15 switched from interferon-β, 15 from glatiramer acetate and 3 from experimental treatments. After a year on teriflunomide treatment, 35 patients showed NEDA and 16 ODA.

We studied changes between basal and 6-month sample. We observed a decreases for the lymphocytes, 75% for ODA (p = 0.004) and 57.14% for NEDA (p= 0.034). They showed a clear decrease for leukocytes 75% for ODA (p = 0.021) and 71.43% for NEDA (p= 0.047). We observed a moderate increase of monocytes in NEDA patiens 40% (p =0.314) and mild increase of monocytes in ODA patients 25% (p = 0.755).

Conclusions

We observe that teriflunomide induces changes in blood immune cells. It was shown a decrease in leukocytes and lymphocytes in both groups and a moderate increase in monocytes in patients with NEDA that we did not find in ongoing disease activity patients.

We did not find a statistically significant correlation between analytical values ​​and response to treatment.

Background

Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in neuronal injury. The terminal complement inhibitor eculizumab is the first treatment approved for use in patients with AQP4 immunoglobulin G-positive NMOSD, based on PREVENT data.

Objectives

To determine whether the beneficial effect of eculizumab in reducing relapse risk in patients with NMOSD is associated with time since diagnosis, relapse history, disability burden or prior immunosuppressant therapy (IST) use, based on data from the phase 3 trial PREVENT (NCT01892345)

Methods

In PREVENT, patients received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo, with stable-dose concomitant IST (except rituximab and mitoxantrone) permitted. PREVENT was not powered for subgroup analyses; post hoc descriptive analysis was performed on subgroups defined by time since diagnosis, total number of historical relapses, baseline Expanded Disability Status Scale (EDSS) score and prior IST use.

Results

The proportions of patients experiencing an adjudicated relapse were lower with eculizumab than with placebo in all subgroups. Proportions for eculizumab and placebo, respectively, were: 2/31 versus 6/12 for < 1 year since diagnosis and 1/65 versus 14/35 for ≥ 1 year since diagnosis; 1/39 versus 10/24 for 2–4 historical relapses and 2/57 versus 10/23 for ≥ 5 historical relapses; 0/14 versus 3/6 for baseline EDSS scores ≤ 2.0 and 3/82 versus 17/41 for baseline EDSS scores ≥ 2.5 to ≤ 7.0; 0/15 versus 2/5 for no prior IST use (except corticosteroids alone); and 3/81 versus 18/42 for prior IST use. Relapse-risk reductions were consistent and statistically significant in all subgroups.

Conclusions

The data from this post hoc subgroup analysis suggest that eculizumab reduced relapse risk in PREVENT compared with placebo, regardless of time since NMOSD diagnosis, relapse history, disability burden or prior IST use.

Background

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, inflammatory disorder associated with relapse activity that may lead to poor recovery. The phase 3 PREVENT study was a randomized controlled trial with an open-label extension (OLE) that evaluated the efficacy of eculizumab in patients with aquaporin-4 immunoglobulin G-positive (AQP4-IgG+) NMOSD. Patients on eculizumab had a significantly lower risk of adjudicated relapse versus patients on placebo and reported improved health-related quality of life (HRQoL). Additional analyses on the impact of relapses on disease progression can provide a basis for the strategic treatment of patients with NMOSD.

Objectives

A post hoc analysis of data from the PREVENT study and its OLE assessed the impact of relapses on disability and HRQoL in patients with AQP4-IgG+ NMOSD.

Methods

Neurological disability was measured via the Expanded Disability Status Scale (EDSS). HRQoL was assessed using the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the 36-Item Short-Form Health Survey (SF-36). Changes in mean scores and the proportion of patients having clinically meaningful worsening (SF-36: 5-point decrease; EDSS: ≥2-point increase if the baseline score was 0, ≥1-point increase if the baseline score was 1 to 5, and ≥0.5-point increase if the baseline score was ≥5.5) from prerelapse to 30, 90, and 120 days post relapse were analysed.

Results

Overall, 27 patients were identified as having ≥1 adjudicated relapse. Compared with prerelapse measures, mean SF-36 PCS and MCS scores were significantly worse at 30 days post relapse, the mean EDSS score was significantly worse at 90 days post relapse, and the mean score for the SF-36 MCS was significantly worse at 120 days post relapse. Between 30 and 90 days post relapse, the proportion of patients with clinically meaningful worsening increased by 7%, 8%, and 11% for the EDSS, SF-36 PCS, and SF-36 MCS, respectively. Between 90 and 120 days post relapse, the proportion of patients decreased by 11% for the EDSS to reach 30%, and increased only by 4% for both the SF-36 PCS and SF-36 MCS to reach 31% and 50%, respectively, suggesting a stabilization of the relapse symptoms.

Conclusions

In the PREVENT study and its OLE, patients with AQP4-IgG+ NMOSD had significant, sustained (120 days) worsening of disability and HRQoL outcomes following adjudicated relapses. One-quarter to one-half of relapsing patients experienced stable, clinically meaningful worsening.

Background

Neuromyelitis optica spectrum disorder (NMOSD) relapses can cause significant and irreversible neurologic disability. In PREVENT, eculizumab reduced the risk of relapse in patients with aquaporin-4 immunoglobulin G-positive (AQP4+) NMOSD by 94.2% vs placebo (hazard ratio 0.058; 95% confidence interval [CI]: 0.017–0.197; p < 0.0001) and adjudicated annualized relapse rate (ARR) for eculizumab was 0.02. The rate of adverse events (AEs)/100 patient-years (PY) was 749.3 for eculizumab and 1160.9 for placebo.

Objectives

To present the long-term efficacy and safety of eculizumab in patients with AQP4+ NMOSD during PREVENT (NCT01892345) and its ongoing open-label extension (OLE; NCT02003144).

Methods

During PREVENT, adults with AQP4+ NMOSD received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo with/without concomitant immunosuppressive therapy (IST). Patients who completed PREVENT could enroll in the OLE to receive eculizumab. Eculizumab safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.

Results

Overall, 137 patients received eculizumab, and were observed for a median (range) of 133.29 (5.1– 276.9) weeks, for a combined total of 362.3 PY. The estimated percentage of patients who were relapse free at 192 weeks (3.7 years) was 94.4% (95% CI: 88.6–97.3). The adjudicated ARR was 0.025 (95% CI: 0.013–0.048) and the annualized relapse-related hospitalization rate (ARRHR) was 0.03/PY (95% CI: 0.017–0.055). Rates of AEs and serious AEs (SAEs)/100 PY were 732.5 and 33.7, respectively. Common AEs included headache (29.2%) and upper respiratory tract infection (27.7%). Common SAEs, excluding NMOSD relapses, were pneumonia (3.6%), urinary tract infection (2.9%) and acute cholecystitis (2.9%). One patient died during PREVENT (pulmonary empyema) and one patient developed a disseminated Neisseria gonorrhoeae infection. In all, 25/137 patients (18.2%) developed a serious infection vs 6/47 (12.8%) receiving placebo in PREVENT. No patient had a meningococcal infection. During the OLE, 50/119 patients (42%) changed concomitant IST; most patients (44/50) stopped or decreased concomitant IST dose.

Conclusions

During PREVENT and its OLE, the percentage of relapse-free patients remained high (94%) through 192 weeks. Eculizumab was well tolerated and AEs were consistent with the safety profile established in other indications. ARRHR was low and many patients were able to reduce or stop concomitant IST.

Background

Aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD) and acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ gMG) are neurological disorders with complement involvement. Eculizumab (a terminal complement inhibitor) demonstrated efficacy in reducing relapse risk and in eliciting clinical improvements during the phase 3, randomized, double-blind PREVENT and REGAIN studies and their open-label extensions (OLEs) (NCT01892345/NCT02003144 [interim data, July 2019] and NCT01997229/NCT02301624) previously published.

Objectives

To compare infection rates in patients with AQP4+ NMOSD or AChR+ gMG receiving eculizumab or placebo with or without concomitant immunosuppressive therapy (IST) during PREVENT, REGAIN and their OLEs.

Methods

Patients were randomized to eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo. Concomitant ISTs, excluding rituximab, were permitted. Post hoc analysis was performed to examine rates of infections in these studies and for subgroups determined by number of ISTs received at baseline.

Results

Rates/100 patient-years (PY) and types of infection were similar in eculizumab and placebo groups. In patients with NMOSD, rates/100 PY and % (n/N), respectively, were: no IST: 176.1, 80.0% (28/35) vs 192.2, 61.5% (8/13); 1 IST: 171.5, 81.8% (45/55) vs 154.1, 63.6% (14/22); 2 ISTs: 186.7, 85.1% (40/47) vs 238.2, 83.3% (10/12). For patients with gMG, rates/100 PY and % (n/N), respectively, were: no IST: 236.8, 100.0% (2/2) vs 305.6, 50.0% (1/2); 1 IST: 228.8, 82.9% (34/41) vs 253.1, 50.0% (9/18); 2 ISTs: 170.5, 91.0% (71/78) vs 192.5, 58.5% (24/41); ≥ 3 ISTs: 97.5, 50.0% (1/2) vs 100.1, 50.0% (1/2). In patients with NMOSD or gMG receiving eculizumab vs placebo, serious infection rates/100 PY and % (n/N), respectively, were: no IST: 2.3, 5.7% (2/35) vs 8.0, 7.7% (1/13) and none observed (0/2 vs 0/2); 1 IST: 11.2, 16.4% (9/55) vs 7.0, 9.1% (2/22) and 16.2, 24.4% (10/41) vs 34.5, 5.6% (1/18); 2 ISTs, 14.8, 29.8% (14/47) vs 47.6, 25.0% (3/12) and 13.4, 21.8% (17/78) vs 24.1, 12.2% (5/41); ≥ 3 ISTs (gMG only), 13.9, 50.0% (1/2) vs 0.0, 0.0% (0/2). One patient with gMG (2 ISTs) had meningococcal meningitis that resolved with antibiotics and eculizumab was resumed.

Conclusions

In AQP4+ NMOSD and AChR+ gMG, infection rates/100 PY were similar in eculizumab and placebo groups, regardless of concomitant IST. Infection rates/100 PY were consistent with the established safety profile of eculizumab.

Background

Disease activity has been investigated in pregnant women with RRMS treated with low-efficacy or no therapy. How newer, more efficacious therapies affect relapse and disability progression risk after pregnancy remains understudied.

Objectives

To describe disease activity in a modern pregnancy cohort contrasted with historical cohorts. To determine the predictors of postpartum relapse and the predictors of six-month confirmed disability progression events in a contemporary pregnancy cohort.

Methods

Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 (modern cohort) were compared with those conceived between 2005-2010 and pre-2005. Annualised relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of time-to-relapse postpartum (1^st 3 months) and time to 6-month confirmed disability progression event were determined with clustered Cox regression analyses. Breastfeeding duration and time to DMT reinitiation were modelled as time-varying covariates.

Results

We included 1640 pregnancies from 1452 women (modern cohort). Disease-modifying therapy (DMT) used in the year before conception included interferon-beta (n=597), natalizumab (n=219) and fingolimod (n=147). Continuation of DMT up to conception increased over time (31% pre-2005 vs 54% modern cohort). Preconception ARR decreased across epochs (pre-2005: 0·58 [95% CI 0·49-0·70]; 2005-2010: 0·40 [95% CI 0·36-0·45]; modern: 0·29 [95% CI 0·27-0·32]). In all epochs, ARR decreased during pregnancy to reach similar troughs in the 3^rd trimester, and rebounded in the 1^st 3-months postpartum. Preconception use of high-efficacy DMT predicted early postpartum relapse (hazard ratio (HR) 2.1 [1.4-3.1]); although those on no DMT were also at risk of postpartum relapse, relative to women on low-efficacy DMT (HR 2.7 [1.2-5.9]). Conception EDSS ≥2, higher preconception and in-pregnancy ARR were also risk factors. DMT reinitiation, particularly of high-efficacy DMT (HR 0.17 [0.07-0.38]), was protective against postpartum relapse. Women who breastfed were less likely to relapse (HR 0.63 [0.42-0.94]). 4.5% of modern pregnancies had confirmed disability progression after delivery. This was predicted by higher pregnancy and postpartum ARR, with postpartum ARR remaining independently predictive in multivariable analysis (HR 1.5 [1.2-2.0]).

Conclusions

The early postpartum period remains a period of vulnerability for disease rebound in women with MS in the modern era. Early DMT reinitiation, particularly with high-efficacy treatment, is protective against postpartum relapse. Confirmed disability progression events after pregnnacy are uncommon in the modern era. Relapse activity is the key driver of these events.

Background

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for the treatment of relapsing and primary progressive multiple sclerosis (MS). As many MS patients are women of reproductive age, pregnancy outcomes in OCR-exposed patients are of relevance.

Objectives

To report an update on pregnancy outcomes in women with MS receiving OCR in clinical trials and post-marketing.

Methods

Analysis includes pregnancies in women receiving OCR in clinical trials/post-marketing (global safety database). Women of childbearing potential should use contraception while on treatment and for 6 or 12 months after the last OCR infusion, depending on local regulations. Based on the average terminal half-life of 26 days and the lack of relevant placental transfer in the 1^st trimester, a fetus was considered to have fetal OCR exposure if the last infusion occurred within 3 months of conception, during pregnancy, or if the date was unknown.

Results

As of March 27, 2020, 726 total pregnancies exposed to OCR in women with MS (n=608) or unknown indication (n=118) were reported. Of the 608 MS pregnancies, 234 were considered to have fetal OCR exposure, 102 were not, and 272 had unknown exposure. Preliminary outcomes of total MS pregnancies (n/%) were: 156/64.2% live births, 37/15.2% elective/therapeutic abortions, 42/17.3% spontaneous abortions, 3/1.2% stillbirths, 5/2.1% ectopic pregnancies; 134 pregnancies were ongoing, 80 lost to follow-up (FU) and 151 had unknown/not reported (NR) outcomes. Of the 156 total live births, 6 congenital malformations were reported. Preliminary outcomes of MS pregnancies with fetal OCR exposure (n/%) were: 62/59.6% live births, 24/23.1% elective/therapeutic abortions, 15/14.4% spontaneous abortions, 2/1.9% stillbirths, 1/1.0% ectopic pregnancies; 55 pregnancies were ongoing, 37 lost to FU and 38 had unknown/NR outcomes. Infant health questionnaires were received from 13 live births with up to 1-year FU and will continue to be collected, including data on vaccinations and infections: 9 infants had no infections and 1 had a resolved infection.

Conclusions

Cases reviewed to date do not suggest an increased risk of adverse pregnancy outcomes (including spontaneous abortions or malformations) with OCR use, whether or not fetal exposure occurred or was unknown. The updated outcomes remain in line with prior reports and within the expected epidemiologic range. Data continue to be collected and assessed as per post-authorization commitments.

Background

There are some controversies about the neonatal anthropometric measures of infants born to MS mothers. Some studies reported a reduction of the head circumference at birth of newborns of MS mothers, which has been associated with developmental delay in other pathologies.

Objectives

To compare head circumference (HC) at birth of newborns of MS mothers with head circumference of newborns of healthy mothers.

Methods

Prospective study in pregnant women and their offsprings. Gestational age and head circumference were analyzed applying 3 different references standards.

Results

We studied 76 women and 96 pregnancies, 90 deliveries and 6 still ongoing. Mean maternal age was 35 ±4 years.

We studied 92 newborns and after excluding preterm and posterm, we analyzed neonatal head circumference of 83 term newborns, 45 girls and 38 boys and mean gestational age of 39.4 ±1 weeks.

Male infants mean HC at birth was 34.8 cm ±1,28 compared with WHO 50th percentile reference of 34.5 cm (p 0.07). Female mean birth HC was 34.6 cm ±0,99, larger than WHO reference of 33.9 cm (p <0.05).

Applying worldwide, the most accepted charts in neonatal centers, Olsen et al. growth curves, that include gender-specific HC-for age curves from infants aged 22 to 42 weeks at birth, we found 9 male infants born at 38 weeks with a mean HC of 34.4 cm ±1.16 the same as the Olsen charts (OC); 13 born at 39 weeks HC mean: 35.3 cm ±1.47 larger than OC (34.6 cm) p 0.12; 8 born at 40 weeks and 6 at 41 weeks HC mean: 34.8 cm ±1.00 and 35.0 cm ±1.55 respectively, the same as the OC in both ages. Analyzing female infants we found; 12 female infants born at 38 weeks with a mean HC of 34.4 cm ±0.76 larger than OC (33.7 cm) p 0.08; 10 born at 39 weeks HC mean: 34.7 cm ±1.11 larger than OC (34.0 cm) (p 0.07); 10 born at 40 weeks HC mean: 34.6 cm ±0.91 compared to 34.3 in OC (p 0.32) and 6 at 41w HC mean: 35.2cm ±0.94 larger than OC charts (34.5 cm) p 0.11.

Spanish pediatric centers usually used the charts of the Orbegozo Foundation^,as standard reference. Comparing our cohort and 50th percentile of the Orbegozo Foundation (35.19 cm ±1.14 for male and 34.48 cm ±1.16 for female) there were no significant findings.

Conclusions

We hence conclude that there were no statistically significant differences in the mean head circumference at birth in newborns of MS mothers compared to different references standard. It is worth highlighting that in order to compare anthropometric measurements in newborns it is crucial to apply standards references that include sex, gestational age and if possible national growth standards to avoid bias, which ultimately are lacking in the WHO standards.

Background

The emergence of a new coronavirus (COVID-19) and the subsequent pandemic present a unique challenge to neurologists managing patients with multiple sclerosis (MS). Preliminary reports do not support an increased risk of severe outcome associated with disease modifying therapies (DMTs) but real-world evidence is lacking.

Objectives

To describe our experience in 14 patients with MS who have been affected by SARS-CoV-2 (with a clinical, RT-PCR, or serological diagnosis) and who were being treated with cladribine in Spain.

Methods

We conducted a consecutive clinical series study including cases occurred in Spain since January 31, 2020 when the first COVID-19 patient was detected in Spain until the end of June 2020.

Results

Patients were mostly female (64%), with an average age of 40.1 (± 12.0) years and a disease duration of 9.7 (± 8.9) years. Median EDSS was 1 (IQR 0–2.5), and the average time on treatment with cladribine was 7.7 (±5.77) months. Two patients had grade 1 lymphopenia, five patients had grade 2 lymphopenia, one patient had grade 3 lymphopenia and six patients were in normal range. Only 1 patient required hospitalization. None required ICU care, or intubation. 93% of the patients improved without any specific treatment. 2 patients (14%) were asymptomatic, 11 (79%) were mild and 1 (7%) was moderate. All recovered without sequelae. 7 of the patients (50%) had a serology test done that showed presence of anti-viral antibodies of IgG and IgM type in all cases.

In our series the patients had a favorable evolution, and all recovered. Factors that could have influenced those results could be the age of the patients, the lack of other risk factors and the mechanism of action of cladribine. It is known that the limited activity of cladribine on cells of the innate immune system and its relatively minor impact on CD8 T cells and plasma cells may have implications for maintained protection from bacterial and viral infections. Importantly, cladribine CD4+ T cell and B cells depletion is partial and transient. The short-term dosing regimen of oral cladribine, potentially reduces depleting effects on the innate immune system.

Conclusions

From this limited number of patients our observations suggest that cladribine treatment does not appear to worsen COVID-19 disease prognosis. MS is a debilitating disease and discontinuing effective treatments might have adverse consequences, benefit/risk assessment is crucial in the current context. Our patients treated with cladribine had an adequate resolution of COVID-19 and mounted an immune response, however more studies are necessary to confirm and extend our preliminary findings.

Background

Sex hormonal variations and age have an influence in the course of the disease. MS patients are getting older and MS and menopausal symptoms could be overlapped and reduce the quality of life of the patients. Therefore is a great need to study the impact of menopause in MS patients.

Objectives

To study menopausal symptoms in MS women, the overlap with the MS symptoms and the influence of the menopause in the disease evolution and the quality of life.

Methods

Retrospective study. MS women with perimenopause and menopause (no more than 5 years) were recruited from our center. We collected demographic information, menarche, DMTs, quality of life, MS and menopause symptoms.

Results

30 patients were included, 15 in perimenopause (mean age 48) and 15 in menopause (mean age 49). 40% of all patients have a decrease of quality of life and increase of depressive symptoms, 50% reported worsening of the disease comparing with the non menopause period.

Most frequent symptoms in menopause MS patients were: Hot flashes (85%), vaginal dryness (70%), weight increase (60%) and adverse mood (60%). 85% of patients have no changes in fatigue, pain, spasticity and urinary symptoms. 31% of patients with menopause reported a worsening of the disease progression. Differences in number of children, menarche, obesity and smoking status have no correlation with an increase of menopausal symptoms. No association between DMTs and worsening or improving menopausal symptoms.

Conclusions

As stated above there is no increase in typical MS symptoms in these patients , however menopausal symptoms are present in most of them, leading to report a worsening in the disease and their well-being. Therefore, it is important to recognize the menopausal symptoms and to treat them to improve the quality of life and well being of our patients.