F. Granella
University of Parma
Department of Medicine and Surgery

Author Of 3 Presentations

 Program
Observational Studies Oral Presentation

PS01.04 - Comparison of disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies

Speakers
Authors
Presentation Number
PS01.04
Presentation Topic
Observational Studies
Lecture Time
11:00 - 11:12

Abstract

Background

to date, no consensus exists on how aggressively and timely treat relapsing-remitting multiple sclerosis (RRMS) patients.

Objectives

To evaluate disability trajectories in a cohort of RRMS patients stratified according to two different disease modifying therapy (DMT) strategies, early intensive treatment (EIT) or moderate-efficacy treatment followed by escalation to higher-efficacy DMT (ESC).

Methods

RRMS patients with ≥5-year follow-up and ≥3 visits after start DMT, and a first visit within 3 years from disease onset were selected from the Italian MS Registry. EIT group included patients who received, as first DMT, fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group included those who received the high efficacy DMT after ≥1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score(PS)-matched for characteristics at the first DMT. The follow-up time from the first DMT start has been segmented into 12-month periods. The disability trajectories were evaluated by applying a longitudinal model for repeated measures with an autoregressive variance-covariance structure. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual EDSS changes compared to baseline values (delta-EDSS) in EIT and ESC groups.

Results

The study cohort included 2,652 RRMS patients from 62 Italian MS centers. The PS matching procedure produced 365 pairs. The median (IQR) follow-up after the first DMT start was 8.5 (6.5–11.7) years. All of the ESC patients escalated to a higher-efficacy DMT after a median time of 5.1 (3.1–8.4) years. The estimated baseline EDSS with relative confidence interval (95% CI) value was 2.52 (2.33-2.71) in the ESC group and 2.45 (2.26-2.64) in the EIT group. Mean delta-EDSS at each 12 month period were all significantly (p<0.02) higher in the ESC group compared to the EIT group. In particular, the mean delta-EDSS differences between the two groups tend to increase from 0.1 (0.01-0.19, p=0.03) at 1 year to 0.30 (0.07-0.53, p=0.009) at 5 years and to 0.67 (0.31-1.03, p=0.0003) at 10 years.

Conclusions

Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression and the effect tends to increase over time despite patients in the ESC group escalated to a higher-efficacy DMT.

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Observational Studies Oral Presentation

PS05.03 - Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort

Speakers
Authors
Presentation Number
PS05.03
Presentation Topic
Observational Studies
Lecture Time
13:27 - 13:39

Abstract

Background

Background: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking, as randomized clinical trials failed to show efficacy in reducing disability progression in this patient population.

Objectives

Objective: To investigate the effectiveness of disease-modifying treatment (DMT) on hard disability outcomes (EDSS 6 and 7) in a real-life population of PPMS patients.

Methods

Methods: Using the Italian MS Registry, we selected PPMS patients with at least three EDSS evaluations and three years of follow-up. Study baseline was defined as the first EDSS evaluation for untreated patients and the date of the first DMT initiation for treated patients. The impact of DMT on the risk of reaching EDSS 6 and 7 was assessed as a dichotomous variable (yes versus no) and as a time-dependent covariate through multivariable Cox regression models (adjusted for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, annualized relapse rate). We compared outcomes with an as-treated analysis and used propensity-score matching (PSM) to select cohorts with comparable baseline characteristics. DMT-exposure was also evaluated in terms of quartiles of exposure.

Results

Results: Of the 1214 patients we included 671 females, mean ± Standard Deviation baseline age 48.7 ± 11.1 years, mean EDSS score 4.1 ± 1.8, 790 (65%) received a DMT during the follow-up (57% platform and 43% highly active treatments). In the whole sample, after a mean follow-up of 11.6 ± 6.3 years, 994 (82%) patients reached EDSS 6 and 539 (44%) EDSS 7. In the multivariable Cox regression models, the use of DMT analyzed as a dichotomous variable did not influence the risk of reaching EDSS 6 (aHR=1.1, 95% CI 0.95-1.28, p=0.181) and EDSS 7 (aHR = 0.93, 95% CI 0.77-1.12. p = 0.454). However, longer DMT exposure significantly reduced the risk of reaching EDSS 7 (aHR = 0.73, 95% CI 0.56-0.95, p =0.021). Of note, patients in the upper quartile of DMT exposure compared with those with shorter DMT exposure were younger at baseline (mean age 44.1 ± 10.6 years; p < 0.001) and received the first DMT closer to the disease onset (mean time to first DMT 6.8 years ± 6.1 ; p=0.002). All these findings were confirmed in the PSM analysis.

Conclusions

Conclusion: Our results suggest that longer exposure to DMT may delay time to wheelchair in PPMS patients. Moreover, treating younger patients and reducing the delay to treatment initiation may improve the patients’ long-term disability outcomes. To optimize treatment decision-making in PPMS further profiling of the best candidates to treatment is needed.

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Gender Differences, Hormones and Sex Chromosomes Oral Presentation

PS12.04 - Pregnancy in a modern day multiple sclerosis cohort: Predictors of relapse during pregnancy

Speakers
Authors
Presentation Number
PS12.04
Presentation Topic
Gender Differences, Hormones and Sex Chromosomes
Lecture Time
10:00 - 10:12

Abstract

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 1st 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 (3rd 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.

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Author Of 8 Presentations

 On-Demand Program
Biostatistical Methods Poster Presentation

P0018 - Variability of the response to immunotherapy among sub-groups of patients with multiple sclerosis (ID 1239)

Speakers
Authors
Presentation Number
P0018
Presentation Topic
Biostatistical Methods

Abstract

Background

Our current understanding of demographic and clinical modifiers of the effectiveness of multiple sclerosis (MS) therapies is limited.

Objectives

To assess whether patients’ response to disease modifying therapies (DMT) in MS varies by disease activity (annualised relapse rate, presence of new MRI lesions), disability, age, MS duration or disease phenotype.

Methods

Using the international MSBase registry, we selected patients with MS followed for ≥1 year, with ≥3 visits, ≥1 visit per year. Marginal structural models (MSMs) were used to compare the hazard ratios (HR) of 6-month confirmed worsening and improvement of disability (EDSS), and the incidence of relapses between treated and untreated periods. MSMs were continuously re-adjusted for patient age, sex, pregnancy, date, time from first symptom, prior relapse history, disability and MRI activity.

Results

Among 23 687 patients with relapsing MS, those on DMT experienced 20% greater chance of disability improvement [HR 1.20 (95% CI 1.0-1.5)], 47% lower risk of disability worsening [HR 0.53 (0.39-0.71)] and 51% reduction in relapses [HR 0.49 (0.43-0.55)]. The effect of DMT on relapses and EDSS worsening was attenuated with longer MS duration and higher prior relapse rate. The effect of DMT on EDSS improvement and relapses was more evident in low EDSS categories. DMT was associated with 51% EDSS improvement in patients without new MRI lesions [HR 1.51 (1.00-2.28)] compared to 4% in those with MRI activity [HR 1.04 (0.88-1.24)]. Among 26329 participants with relapsing or progressive MS, DMT was associated with 25% reduction in EDSS worsening and 42% reduction in relapses in patients with relapsing MS [HR 0.75 (0.65-0.86) and HR 0.58 (CI 0.54-62), respectively], while evidence for such beneficial effects of treatment in patients with progressive MS was not found [HR 1.11 (0.91-1.46) and HR 1.16 (0.91-1.46), respectively].

Conclusions

DMTs are associated with reduction in relapse frequency, progression of disability, and increased chance of recovery from disability. In general, the effectiveness of DMTs was most pronounced in subgroups with shorter MS duration, lower EDSS, lower relapse rate and relapsing MS phenotype.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0314 - Dimethyl fumarate-induced lymphocyte count drop is related to clinical effectiveness in relapsing-remitting multiple sclerosis (ID 853)

Speakers
Authors
Presentation Number
P0314
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Dimethyl fumarate (DMF) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS) patients. Besides a partially known mechanism of action involving both neuroprotective and antioxidant effects, it causes a mean lymphocyte count drop of approximately 30%, typically occurring within the first year of treatment. Several studies investigated the relationship between this reduction and DMF effectiveness, with heterogeneous methods, obtaining contradictory results.

Objectives

To investigate if absolute lymphocyte count (ALC) decrease during DMF treatment is associated with drug effectiveness on clinical and MRI disease activity in a real-life cohort of patients treated with DMF for at least 6 months. Secondary aims were to evaluate ALC variations over time and the impact of baseline demographic and clinical factors on DMF-induced lymphopenia.

Methods

Demographic, laboratory, clinical and MRI data were collected in this retrospective, observational multicentre study, conducted on RRMS patients attending nine MS centers of Emilia-Romagna region (Northern Italy). Multivariate Cox models were performed to evaluate the impact of six month-ALC drop on time to NEDA-3 (“no evidence of disease activity”) status loss and Kaplan-Meier curves were generated to display the results. Multivariate logistic regression was carried out to analyse possible predictors of lymphopenia.

Results

476 patients (312 females, age at DMF start 38.4 ± 9.97 years) were analysed during a mean follow-up time of 29 months (range 6-61 months). A greater lymphocyte decrease was associated with a longer NEDA-3 status (HR 0.87, p = 0.01), relapse-free (HR 0.85, p = 0.03) and MRI activity-free survival (HR 0.80, p < 0.0001). A higher risk of NEDA-3 status loss (p=0.008) was observed in tertile with lower ALC drop (< 11.5%), compared with other tertiles (11.5-40.5% and >40.5% ALC drop, respectively). A shorter activity-free survival was also influenced by younger age at DMF start (HR 0.98, p = 0.03). The nadir of mean ALC drop (-33.6%) and 35% of grade III lymphopenia cases occurred after 12 months of treatment. An older age at DMF start (OR 1.03, 95% CI 1.00-1.06, p = 0.009) and lower ALC at baseline (OR 1.69, 95% CI 1.34-2.14, p < 0.0001) predicted higher risk of lymphopenia.

Conclusions

A higher lymphocyte count drop at six months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24 months of treatment.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0363 - Ocrelizumab as exit strategy from natalizumab: results from a clinical series (ID 854)

Speakers
Authors
Presentation Number
P0363
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting (RR) multiple sclerosis (MS), but its prolonged use can be associated with an increased risk of progressive multifocal leukoencefalopathy (PML). Therefore, NTZ is mainly interrupted in the context of PML risk management strategy, but its discontinuation can be followed by a marked increase of disease activity. Currently, there is no consensus on either the duration of the washout period, or the best subsequent treatment approach. Few data are available on the use of anti-CD20 monoclonal antibodies (mostly rituximab) after NTZ withdrawal, whereas only a small case series of patients switching to ocrelizumab (OCR) has been published in literature.

Objectives

To evaluate the effectiveness, tolerability and safety of OCR in a real-world cohort of MS patients switching from NTZ.

Methods

Demographic, laboratory, clinical and MRI data were collected in this retrospective, observational study, performed on MS patients attending Parma MS centre (Northern Italy).

Results

23 patients (14 females, mean age 40.4 ± 8.57 years) were analysed during a mean follow-up of 15 months (range 5-34), since NTZ discontinuation. Patients had the following characteristics at OCR start: RR course in 74% and progressive active disease in 26%, mean EDSS 3.1 (1.5-6.5), mean disease duration 11 ± 5.67 years and median number of NTZ infusions 28 (13-122). The reasons for switch included PML concern in 78% of cases and suboptimal response to NTZ in 22%. The majority (83%) of patients was JCV+ and only 6 were treated with NTZ extended interval dosing for ≥18 months. The median washout period was 50 days (41-251); all patients underwent a brain MRI immediately before OCR start. Only 4/23 (17%) and 1/19 (5%) patients experienced clinical relapses (all within the first 6 months of therapy) and MRI activity, respectively. ARR decreased from 0.41 (during NTZ) to 0.18 with OCR. Mild adverse events (mostly infusion reactions, hypogammaglobulinemia and leukopenia) occurred in 74% of cases. No patients discontinued OCR and no PML cases emerged.

Conclusions

OCR is effective and well tolerated in highly active MS patients switching from NTZ. A median 6-week transition period appears reasonably safe to balance the risk of disease reactivation with that of opportunistic infections. Larger datasets are needed to confirm the risk of carryover PML in relationship with the length of washout period.

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Epidemiology Poster Presentation

P0506 - Towards a validated Secondary Progressive Multiple Sclerosis definition: A study from the Italian MS Register (ID 1432)

Speakers
Authors
Presentation Number
P0506
Presentation Topic
Epidemiology

Abstract

Background

No clear metrics for sensitive and reliable identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive (SP)MS are available.

Objectives

To compare diagnostic performances of two different data-driven Secondary Progressive Multiple Sclerosis definitions.

Methods

patient with RRMS with a follow-up ≥5 years, with a current age ≥18 years, and with ≥3 EDSS scores recorded were selected from the Italian MS Registry. Annual incidence of SPMS conversion was reported as number of patients converting to SP every 100 patients/year. Three different SPMS definitions have been used. Data-driven definitions based on the Lorscheider’s algorithm (LA) and on the EXPAND trial inclusion criteria were validated, using the neurologist’s definition as gold standard, in terms of calibration, discrimination and goodness of fit by calculating: sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), the Akaike information criterion (AIC), the Area Under the Curve (AUC). The overall calibration of the data-driven definitions was evaluated by the Calibration Slope test.

Results

a cohort of 10,240 RRMS patients was extracted from the Italian MS Registry. According to the neurologist judgment, 880 (8.59%) patients were classified as SPMS in the dataset. By applying the LA and the EXPAND definition, 1,806 (17.64%) and 1,134 (11.07%) patients, respectively, were classified as SPMS. The annual rate of SP conversion during the follow-up was 0.74 every 100 patients/year based on the neurologist’s definition, 1.57 every 100 patients/year using the LA and 0.94 every 100 patients/year applying the EXPAND definition. Both the data-driven definitions were well calibrated, with a p-value of the Calibration Slope test higher than 0.05 (LA=0.55; EXPAND definition=0.57). The AIC (LA=4301; EXPAND definition=5510) and the R-Square (LA=0.15 vs EXPAND definition=0.05), were in favor of the LA. The LA showed a greater discrimination power (AUC: 0.83 vs 0.65) and a higher sensitivity (77.1% vs 38.0%) in comparison to the EXPAND definition. Both definitions showed similar specificity (88.0% vs 91.5%). The PPV and the NPV were both higher using the LA than those obtained by the EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%, respectively).

Conclusions

An accurate definition of SP transition is needed for a timely and efficacious treatment of SPMS patients. Real-world data from the Italian MS Registry suggests that data-driven definitions had a greater ability to capture SP transition than neurologist’s definition and that the global accuracy of LA seems to be higher than a definition based on the EXPAND trial inclusion criteria.

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Imaging Poster Presentation

P0600 - Longitudinal evolution of cortical lesions in an Italian cohort of multiple sclerosis patients (ID 731)

Speakers
Authors
Presentation Number
P0600
Presentation Topic
Imaging

Abstract

Background

Cortical lesions (CLs) have recently acquired a great relevance in multiple sclerosis (MS), both at diagnosis and during the monitoring of the disease, because of their impact on long-term prognosis. However, there is still limited knowledge about the evolution of CLs in time.

Objectives

The aim of the present observational study was to investigate, retrospectively, the longitudinal evolution of CLs number in comparison to FLAIR-T2 hyperintense white matter lesions (WMLs) in a cohort of MS patients in a single MS centre.

Methods

We included all consecutive patients with a relapse-onset MS referred to MS centre of Parma (Italy) who performed at least two MRI scans including double inversion recovery sequences from 2014 to 2019, collecting demographic, clinical and MRI data.

Results

We included 140 MS patients, 67.9% female, with the following characteristics at first MRI: relapsing-remitting (RR) course in 84.3% and secondary progressive (SP) in 15.7% of cases, mean age 40.1±10.49 years, mean disease duration 169.7±100.75 months, mean EDSS 2.5±1.30, mean number of WMLs 24.8±16.50 and of CLs 2.5±2.87. After a mean follow-up of 51.8±8.32 months we observed a conversion to SP phase in 2.1% and a 3-mo-confirmed EDSS progression in 13.6% of patients, with a mean EDSS of 2.6±1.48 and mean number of relapses of 1.1±1.95. During the follow-up only 3.6% of patients did not take any therapy, while 47.1% and 49.3% were on a first-line and a second-line disease-modifying treatment (DMT), respectively. Occurrence of ≥1 new WML or CL appeared in 37.9% and 12.9% of cases, respectively, with a mean number of new WMLs of 1.8±5.58 and new CLs of 0.2±0.6. New CLs never appeared without concomitant WMLs, but 44.4% of cases with new CLs occurred in patients with 1-2 new WMLs and 26.7% of patients with 1-2 new WMLs had ≥1 new CL. At multivariate analysis the risk of occurrence of new CLs was higher in patients with a higher number of new WMLs at last MRI (OR 1.44, CI95% 1.17-1.78, p=0.001) and lower in those who remained RR (OR 0.04, CI95% 0.002-0.76, p=0.03).

Conclusions

In our cohort we observed an overall low MRI activity, probably related to the high percentage of patients on DMT. New CLs appeared in a small percentage of patients and were strictly related to new WMLs. Nevertheless, they added clinical relevance to a consistent proportion of cases characterised by otherwise minimal MRI activity, with important implications for therapeutic switch.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0759 - Treatment patterns in patients with neuromyelitis optica spectrum disorder (ID 1400)

Speakers
Authors
Presentation Number
P0759
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Many patients with neuromyelitis optica spectrum disorder (NMOSD) are managed using off-label immunosuppressants for relapse prevention, and treatment guidelines are based on small, often uncontrolled, studies with low levels of evidence.

Objectives

To assess real-world treatment patterns in patients with NMOSD.

Methods

Based on the global NMOBase cohort, patients diagnosed with NMOSD between 2006–2019 per the international 2015 consensus criteria and with ≥2 Expanded Disability Status Scale scores recorded at different visits were included in the study population. The aquaporin-4 autoantibody (AQP4-IgG) serostatus was determined mainly by cell-based assay; treatment sequence for maintenance therapies was assessed in seropositive (AQP4-IgG+) patients only. The date of biomarker testing was used as a proxy for diagnosis date and served as the baseline for the observational period.

Results

The study population included 334 NMOSD patients tested for AQP4-IgG serostatus. Among them, 301 (90.1%) were AQP4-IgG+. Mean age was 45.3 years; 84.1% were women and 51.8% (n=156) came from Europe. Two thirds had ≥5 visits recorded in NMObase, and the mean observational period was 4.8 years. Five treatment lines (1L–5L) were observed, with only 1.3% of the AQP4-IgG+ cohort (n=4) progressing to the last line. At baseline, the most common therapy was azathioprine (23.6%) followed by rituximab (5.3%), and 65.4% (n=197) were not prescribed any disease-modifying therapy (DMT). The median time between the test date and initiation of DMT was 3.2 months, although 25% of patients waited >10 months. Most AQP4-IgG+ patients (66.4%; n=200) progressed beyond 1L. The most frequent treatments at 2L were rituximab (43.5%) and azathioprine (41.0%). The proportion receiving rituximab, the predominant therapy beyond 2L, remained stable at 3L (48.1%; n=25) and 4L (46.7%; n=7). Across all treatment lines, there were anecdotal reports of use of DMT indicated for multiple sclerosis (MS) (e.g., betaferon), possibly reflecting old clinical practice. A large proportion (83.4%) received corticosteroids, either as acute relapse- or maintenance- therapy, along their treatment pathway.

Conclusions

Based on data collected before recent drug approvals, the main treatment options included off-label drugs and a few MS DMTs. A quarter of patients did not initiate NMOSD DMTs for >10 months from diagnosis. Newly approved therapies might partly address this unmet need, at least for AQP4-IgG+ patients.

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Observational Studies Poster Presentation

P0862 - Disability accrual in primary-progressive & secondary-progressive multiple sclerosis (ID 1232)

Speakers
Authors
Presentation Number
P0862
Presentation Topic
Observational Studies

Abstract

Background

Some cohort studies have reported similar onset age and disability accrual in primary and secondary progressive MS (PPMS, SPMS); others have reported later onset and faster disability accrual in SPMS. Comparisons are complicated by differences in baseline disability and exposure to disease-modifying therapies (DMT), and by lack of a standardized definition of SPMS.

Objectives

We compared hazards of disability accrual in PPMS and SPMS patients from the MSBase cohort using multivariable Cox models, applying validated diagnostic criteria for SPMS (Lorscheider et al., Brain 2016).

Methods

Inclusion required adult-onset progressive MS; ≥ 3 recorded Expanded Disability Status Scale (EDSS) scores; and, for SPMS, initial records with EDSS ≤ 3 to allow objective identification of SPMS conversion. Phenotypes were subgrouped as active (PPMS-A, SPMS-A) if ≥ 1 progressive-phase relapse was recorded, and inactive (PPMS-N, SPMS-N) otherwise. Disability accrual was defined by sustained EDSS increases confirmed over ≥ 6 months. Hazard ratios (HR) for disability accrual were obtained using Andersen-Gill Cox models, adjusted for sex and time-varying age, disability, visit frequency, and proportion of time on DMT or immunosuppressive therapy. Sensitivity analyses were performed using (1) PPMS and SPMS diagnosed since 1995, and (2) physician-diagnosed SPMS. Cumulative probability of reaching EDSS ≥ 7 (wheelchair required) was assessed (Kaplan-Meier).

Results

5461 patients were included (1257 PPMS-N; 1308 PPMS-A; 1731 SPMS-N; 1165 SPMS-A). Age at progression onset was older in SPMS than PPMS (47.2 ± 10.2, vs. 41.5 ± 10.7 [mean ± SD]), and in the inactive subgroups of each phenotype. Hazard of disability accrual was decreased in SPMS relative to PPMS (HR 0.85; 95% CI 0.78–0.92); decreased by proportion of time on DMT (HR 0.99 per 10% increment; 0.98–0.99); and higher in males (1.18; 1.12–1.25). Relative to PPMS-N, hazard was decreased in SPMS-A (0.79; 0.71–0.87) but similar for PPMS-A (1.01; 0.93–1.10) and SPMS-N (0.94; 0.85–1.05). Sensitivity analyses corroborated these results. However, patients with SPMS-A reached EDSS ≥ 7 at younger ages (cumulative probability 30% by 57, vs. 64–66 for SPMS-N, PPMS-A, PPMS-N).

Conclusions

Progressive phase onset is later in SPMS than PPMS. Hazard of disability accrual during the progressive phase is lower in SPMS than PPMS. However, patients with SPMS-A reach wheelchair requirement younger than other progressive phenotypes, reflecting earlier progression onset versus SPMS-N, and greater disability at onset versus PPMS

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Reproductive Aspects and Pregnancy Poster Presentation

P1131 - Pregnancy in a modern day multiple sclerosis cohort: Predictors of postpartum relapse and disability progression (ID 1321)

Speakers
Authors
Presentation Number
P1131
Presentation Topic
Reproductive Aspects and Pregnancy

Abstract

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 (1st 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 3rd trimester, and rebounded in the 1st 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.

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