Author Of 2 Presentations
PS01.04 - Comparison of disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies
- P. Iaffaldano
- G. Lucisano
- F. Caputo
- D. Paolicelli
- F. Patti
- M. Zaffaroni
- V. Brescia Morra
- C. Pozzilli
- G. De Luca
- M. Inglese
- G. Salemi
- C. Florio
- E. Cocco
- P. Sola
- G. Lus
- A. Conte
- M. Amato
- F. Granella
- S. Galgani
- D. Centonze
- R. Totaro
- M. Rovaris
- M. Salvetti
- R. Mantegazza
- R. Bergamaschi
- D. Maimone
- E. Scarpini
- A. Bertolotto
- G. Comi
- M. Filippi
- M. Trojano
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.
PS05.03 - Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort
- M. Fonderico
- E. Portaccio
- P. Iaffaldano
- L. Pastò
- L. Razzolini
- A. Bellinvia
- R. Fratangelo
- L. Tudisco
- G. De Luca
- P. Ragonese
- F. Patti
- V. Brescia Morra
- E. Cocco
- P. Sola
- M. Inglese
- G. Lus
- C. Pozzilli
- D. Maimone
- A. Lugaresi
- P. Gazzola
- G. Comi
- I. Pesci
- D. Spitaleri
- M. Rezzonico
- M. Vianello
- C. Avolio
- F. Logullo
- F. Granella
- M. Salvetti
- M. Zaffaroni
- C. Guaschino
- A. Ghezzi
- G. Lucisano
- M. Filippi
- M. Trojano
- M. Amato
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.
Author Of 6 Presentations
LB1158 - COVID-19 pandemic and mental distress in Multiple Sclerosis: implications for clinical management (ID 1300)
Abstract
Background
in multiple sclerosis (MS), disease-related factors and dysfunctional coping might favour the development of mental distress induced by COVID-19 containment measures.
Objectives
to explore the relationship between mental distress, disability and coping strategies in the Italian MS population under lockdown.
Methods
Structural equation modeling (SEM) was applied to information collected via web-survey to identify modifiable factors that could account for mental distress. Information about the following domains was collected: (1) socio-demographic features; (2) general and MS related health status; (3) changes in lifestyle; (4) COVID-19 infection and risk perception; (5) physical disability assessed via the Patient-Determined Disease Steps (PDDS) scale and the Upper Extremity Function – Short Form (UEF) from the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system; (6) cognitive function investigated using the Cognition Function– Short Form from the Neuro-QoL. Abstract reasoning, logical thinking and, in part, sustained attention, were measured using six Raven-like matrices; (7) mental distress: four domains from the Neuro-QoL were explored. Specifically, sleep disturbances, anxiety feelings, depressive symptoms, emotional dyscontrol; (8) coping strategies: individual response to lockdown was assessed using 18 items from the COPE-NVI-25, evaluating five independent coping strategies: avoidance (AV), social support (SS), positive attitude (PA), problem solving (PS) and turning to religion (TR).
Results
845 subjects (497 MS and 348 controls) were included in the study. MS patients showed higher scores than controls for depression (p=0.005), but not for anxiety, emotional dyscontrol or sleep disturbances. The SEM explained 74% of the variance observed in depression score. Within the model, three latent factors were characterized from measured variables: motor disability and cognitive dysfunction contributed to disability (β=0.509 and β=0.836, p<0.001); positive attitude and exercise contributed to active attitude (β=0.386 and β=0.297, p<0.001); avoidance, social support and watching TV contributed to passive attitude (β=0.301, β=0.243 and β=0.212, p<0.001). As per the relationship between latent factors and their influence on depression, disability contributed to passive attitude (β=0.855, p<0.001) while both passive and active attitude significantly influenced depression (β=0.729 and β=-0.456, p<0.001).
Conclusions
As practical implication of our model, favoring exercise would enhance active attitude and its positive impact on mental well-being while, at the same time, reducing the negative impact of disability on depression, representing a valuable tool for the long term management of COVID-19 related mental distress in MS.
LB1191 - Validation of the Italian version of the Multiple sclerosis intimacy and sexuality questionnaire-19 (ID 1991)
Abstract
Background
People with Multiple sclerosis (MS) may experience sexual dysfunction throughout the disease course. Prevalence for sexual dysfunction in MS ranges from 70 to 90 %, higher than in healthy controls (about 50%). Clinicians do not always ask for sexual dysfunction both for the limited timeframe for clinical assessment and the intimate nature of the subject. Hence, the use of self-reported questionnaires would be useful in clinical practice. However, validated scales to assess sexual dysfunction in MS for Italian patients are lacking.
Objectives
We aimed at validating Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSISQ-19) for Italian MS patients.
Methods
We included both male and female MS patients. Each patient completed the Italian translation of the MSISQ-19, the Beck Depression Inventory (BDI-II), the Modified Fatigue Impact Scale (MFIS), the State-Trait Anxiety Inventory (STAI-Y) questionnaire, the International Consultation on Incontinence Questionnaire Lower Urinary Tract Symptoms Quality of Life Module (ICIQ-LUTSqol), the Female Sexual Function Index (FSFI, for female) and the International Index of Erectile Function (IIEF for male). Construct validity for the Italian version of the MSISQ-19 was explored by the exploratory factor analysis and the Cronbach’s alpha coefficient. Test-retest stability and concurrent internal and external validity was examined by Pearson’ correlation coefficients.
Results
We enrolled 369 MS patients (323 female). Mean MSISQ-19 total score was 37.2 ± 15.2 (range 18 - 89) with a sexual dysfunction prevalence of 59% in male MS patients and 41% in female MS patients. Cronbach’s alpha was 0.92 for the MSISQ-19. MSISQ-19 test and retest total scores correlated between each other (r=0.48, p=0.01). MSISQ-19 total score also correlated with primary, secondary and tertiary subscales (p<0.001), with the EDSS (r=0.19, p<0.001) and all other neuropsychological scales.
Conclusions
The Italian Version of the MSISQ-19 showed satisfactory internal consistency and reliability with moderately adequate test-retest reproducibility, suggesting that the Italian MSISQ-19 questionnaire provides a valuable measure of sexual dysfunction in the Italian population.
LB1193 - The Framingham cardiovascular risk score and 5-year progression of multiple sclerosis (ID 2012)
Abstract
Background
Cardiovascular risk factors and comorbidities can affect the prognosis of multiple sclerosis (MS). The Framingham risk score is an algorithm that can estimate the 10-year risk of developing macrovascular disease.
Objectives
To evaluate possible association between the Framingham risk score at baseline, and MS relapses, disability and disease-modifying therapy choices over 5-year follow-up.
Methods
This is a retrospective cohort study including 251 MS subjects. At baseline, we calculated the Framingham risk score considering the following variables: age, sex, diabetes, smoking, systolic blood pressure, and body mass index. MS outcomes including relapses, disability and treatments were collected over 5 years. Cox proportional regression models were employed to estimate hazard ratios (HR).
Results
1-point increase in the Framingham risk score was associated with 31% higher risk of relapse (HR=1.31; 95%CI=1.03, 1.68), 19% higher risk of reaching of EDSS 6.0 (HR=1.19; 95%CI=1.05, 3.01), and 62% higher risk of disease modifying treatment escalation (HR=1.62; 95%CI=1.22, 3.01).
Conclusions
Higher cardiovascular risk was associated with higher risk of relapses, disability, and treatment escalation in MS. Early identification, correction and treatment of cardiovascular comorbidities should be carefully considered within MS management.
P0506 - Towards a validated Secondary Progressive Multiple Sclerosis definition: A study from the Italian MS Register (ID 1432)
- P. Iaffaldano
- G. Lucisano
- M. Filippi
- G. Comi
- M. Onofrj
- F. Patti
- V. Brescia Morra
- M. Zaffaroni
- C. Pozzilli
- E. Cocco
- P. Sola
- G. Salemi
- M. Inglese
- R. Bergamaschi
- S. Galgani
- M. Amato
- A. Conte
- M. Salvetti
- G. Lus
- C. Florio
- R. Totaro
- M. Vianello
- F. Granella
- E. Ferraro
- U. Aguglia
- M. Gatto
- B. Orlando
- F. Sangalli
- G. De Luca
- C. Chisari
- A. Carotenuto
- D. Baroncini
- D. Colombo
- M. Nica
- D. Paolicelli
- M. Trojano
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.
P0656 - Unraveling deep grey matter atrophy, iron and myelin changes in Multiple Sclerosis (ID 1287)
Abstract
Background
Modifications of magnetic susceptibility, seemingly reflecting iron accumulation/depletion, have been consistently demonstrated in subcortical gray matter (GM) of MS patients, but some questions remain unanswered regarding the underlying neurobiological processes and their clinical relevance.
Objectives
to disentangle the contribution of atrophy, iron and myelin changes to deep GM (DGM) damage in MS, simultaneously exploring their relationship with clinical disability through the application of quantitative susceptibility mapping (QSM) and longitudinal relaxation rate (R1) relaxometry.
Methods
In this cross-sectional study, 91 patients and 55 healthy controls were imaged with 3T MRI to compute QSMs and R1 maps, from which iron and myelin concentration maps were estimated by applying an external model. Modifications of DGM iron and myelin (mean concentration-dependent from atrophy and total content-independent from atrophy) were investigated at both global and regional levels. Significantly altered MRI features were tested as disability predictors in hierarchical linear regression models.
Results
Compared to controls, MS patients showed reduced thalamic(p<0.001) and increased pallidal(p<0.001) iron concentrations. No differences emerged regarding total myelin or iron content in the basal ganglia, while actual iron depletion was found in the thalamus(p<0.001). At the voxel-based analysis, patients showed increased iron concentration in the basal ganglia(p≤0.001) and reduced iron and myelin local content in thalamic posteromedial regions(p≤0.004), corresponding to reduced iron and myelin content in the pulvinar(p≤0.001) at the subnuclei analysis. Thalamic volume(B=-0.341,p=0.02), iron concentration(B=-0.379,p=0.005) and content(B=-0.406,p=0.009) significantly predicted disability, as well as pulvinar iron(B=-0.415,p=0.003) and myelin(B=-0.406,p=0.02) content, independently of atrophy.
Conclusions
Quantitative MRI suggests an atrophy-related iron increase within the basal ganglia of MS patients, along with an absolute reduction of thalamic iron and myelin, which correlates with disability. Atrophy-independent depletions of thalamic iron and myelin may represent clinically relevant, sensitive markers of subcortical GM damage.
P0913 - Risks associated with wash-out duration when switching from fingolimod to cell-depleting agents (ID 1317)
Abstract
Background
A wash-out duration lasting >1–2 months between the majority of sequential disease-modifying therapies (DMTs) is associated with an increased risk of disease reactivation in Multiple Sclerosis (MS) patients.
Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes 1-2 months. It has been hypothesized that the therapeutic effects of subsequent cell-depleting agents may be compromised if lymphocyte recovery is still incomplete and that shorter wash-out periods do not affect the disease reactivation risk.
Objectives
To assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent initiation in relation to the duration of wash-out between the drugs using data from the Italian MS Registry.
Methods
Patients who initiated alemtuzumab, rituximab, ocrelizumab or cladribine within six months of FTY discontinuation, and with a follow-up of at least six months, or until a relapse occurred, were included in the study. The risk of relapses was assessed in relation to different wash-out durations (<6, 6-11, 12-17 and >/=18 weeks) using a Poisson regression analysis (and reported as incidence rate ratio - IRR) and a Cox proportional hazards model including age, disease duration, relapses during FTY treatment, EDSS and reason for FTY discontinuation as covariates.
Results
Inclusion criteria were met by 329 patients (226F, 103M; mean age 41±10 years). Following a median wash-out period of 11 weeks [IQR: 6-16], 175 patients started alemtuzumab, 69 rituximab, 68 ocrelizumab and 17 cladribine. Ninety patients relapsed during the wash-out period and 72 during the subsequent cell-depleting therapy. During the cell-depleting treatment, IRR for a relapse was significantly greater in patients with a washout-period of 12-17 (IRR (95%CI): 2.4 (1,1-5,5); p=0.037) and >/=18 weeks (6.0 (2.8-12.7); p<0.001) compared to the reference period (<6 weeks).
The multivariable Cox analysis showed that the time to a relapse was significantly influenced by the occurrence of relapses during FTY treatment (HR (95%CI): 1.4 (1.2-1.7); p<0.001). Moreover, wash-out durations of 6-11, 12-17 and >/=18 weeks were associated with a higher risk of a relapse in comparison to wash-out durations shorter than 6 weeks (3.8 (1.1-13.2); p=0.037; 6.0 (1.7-21.9); p=0.006; 16.3 (4.8-56.3); p<0.001, respectively).
Conclusions
The risk of relapses during a cell-depleting therapy following a sequestering agent, namely FTY, increases progressively with the duration of wash-out, underlining the need of a short wash-out period also in this type of treatment sequence.