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Observational Study
. 2021 Jun 1;78(6):726-735.
doi: 10.1001/jamaneurol.2021.1008.

Risk of Persistent Disability in Patients With Pediatric-Onset Multiple Sclerosis

Damiano Baroncini  1 , Marta Simone  2 , Pietro Iaffaldano  3 , Vincenzo Brescia Morra  4 , Roberta Lanzillo  4 , Massimo Filippi  5 , Marzia Romeo  6 , Francesco Patti  7 , Clara Grazia Chisari  7 , Eleonora Cocco  8 , Giuseppe Fenu  8 , Giuseppe Salemi  9 , Paolo Ragonese  9 , Matilde Inglese  10   11 , Maria Cellerino  10 , Lucia Margari  2 , Giancarlo Comi  1   12 , Mauro Zaffaroni  1 , Angelo Ghezzi  1 ; Italian MS registry
Collaborators, Affiliations
Observational Study

Risk of Persistent Disability in Patients With Pediatric-Onset Multiple Sclerosis

Damiano Baroncini et al. JAMA Neurol. .

Abstract

Importance: Availability of new disease-modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear whether this improvement also involves patients with pediatric-onset MS (POMS), whose early management is more challenging.

Objective: To evaluate changes in the prognosis of POMS over time in association with changes in therapeutic and managing standards.

Design, setting, and participants: Retrospective, multicenter, observational study. Data were extracted and collected in May 2019 from the Italian MS Registry, a digital database including more than 59 000 patients. Inclusion criteria were MS onset before age 18 years, diagnosis before January 2014, and disease duration of at least 3 years. Exclusion criteria were primary progressive MS, Expanded Disability Status Scale (EDSS) score of at least 8 one year after onset, unavailability of diagnosis date, and less than 2 EDSS score evaluations. Eligible patients were 4704 patients with POMS. According to these criteria, we enrolled 3198 patients, excluding 1506.

Exposures: We compared time to reach disability milestones by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006, and 2007-2013), adjusting for possible confounders linked to EDSS evaluations and clinical disease activity. We then analyzed the difference among the 4 diagnosis epochs regarding demographic characteristics, clinical disease activity at onset, and DMTs management.

Main outcomes and measures: Disability milestones were EDSS score 4.0 and 6.0, confirmed in the following clinical evaluation and in the last available visit.

Results: We enrolled 3198 patients with POMS (mean age at onset, 15.2 years; 69% female; median time to diagnosis, 3.2 years; annualized relapse rate in first 1 and 3 years, 1.3 and 0.6, respectively), with a mean (SD) follow-up of 21.8 (11.7) years. Median survival times to reach EDSS score of 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS score of 4.0 (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83 in 1993-1999; HR, 0.48; 95% CI, 0.38-0.60 in 2000-2006; and HR, 0.44; 95% CI, 0.32-0.59 in 2007-2013) and 6.0 (HR, 0.72; 95% CI, 0.57-0.90; HR, 0.44; 95% CI, 0.33-0.60; and HR, 0.30; 0.20-0.46). In later diagnosis epochs, a greater number of patients with POMS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time.

Conclusions and relevance: In POMS, the risk of persistent disability has been reduced by 50% to 70% in recent diagnosis epochs, probably owing to improvement in therapeutic and managing standards.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Baroncini received travel grants for participation at national/international congresses and compensations for consulting/speaking/scientific publications activities from Sanofi Genzyme, Teva, Merck, Biogen, Roche, Almirall, and Novartis. Dr Iaffaldano has served on scientific advisory boards for Biogen, Novartis, Roche, Merck, and Genzyme; has received speaker honoraria from Biogen Idec, Merck, Roche, Teva, Sanofi Genzyme, and Novartis; and has received research grants for his institution from Biogen Idec, Merck, Roche, and Novartis. Dr Brescia Morra has acted as paid consultant and has received funding for research from Merck, Novartis, Teva, Mylan, Roche, Biogen, and Sanofi. Dr Lanzillo has acted as paid consultant and has received funding for research from Merck, Novartis, Teva, Mylan, Roche, Biogen, and Sanofi. Dr Filippi is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries; and still receives research support from Biogen Idec, Merck Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Dr Romeo received honoraria from Sanofi Genzyme and Merck Serono and support for traveling from Novartis, Almirall, and Teva Pharmaceutical Industries. Dr Patti served on the advisory board for Bayer, Biogen Celgene, Merck, Novartis, Roche, Sanofi, Teva, and Almirall. He also received personal fees for speaking activities at congresses or sponsored symposia. Dr Chisari has received grants for congress participation from Almirall, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva. Dr Salemi received personal fees for speaking activities from Bayer Biogen, Merck, Novartis, and Teva. Dr Ragonese received travel expenses or honoraria for consultancy from Merck Serono, Biogen, Novartis, Sanofi Genzyme, and Teva. Dr Inglese received honoraria or consultation fees from Roche, Biogen, Merck Serono, and Genzyme and research grants from the National Institutes of Health, National Multiple Sclerosis Society, Fondazione Italiana Sclerosi Multipla, Novartis, and Teva Neuroscience. Dr Comi has received a compensation for consulting services and/or speaking activities from Novartis, Teva, Sanofi Genzyme, Merck, Roche, Almirall, Celgene, Forward Pharma, MedDay, and EXCEMED. Dr Zaffaroni has received honoraria for lecturing or participating for advisory boards or travel funding from Almirall, Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Teva. Dr Ghezzi has served on scientific advisory boards of Merck Serono, Sanofi-Genzyme, Novartis, Mylan, Biogen, and Teva and has received speaker honoraria from Merck Serono, Teva, Biogen Idec, Sanofi Genzyme, Novartis, Serono Symposia International, and Almirall.

Figures

Figure 1.
Figure 1.. Recruitment of Patients With Pediatric-Onset Multiple Sclerosis (MS)
We included in this study 3198 patients with pediatric-onset MS from the Italian MS registry, with more than 59 000 patients with MS at May 2019. Each excluded patient could have more than 1 exclusion criterion.
Figure 2.
Figure 2.. Time to Reach Disability Milestones from MS Onset Compared by Diagnosis Epochs
A and C, Kaplan-Meier survival plots, stratified by diagnosis epochs. Number of total events (ie, number of patients who reached the Expanded Disability Status Scale [EDSS] milestone) was 1046 (32%) for EDSS score of at least 4 and 628 (20%) for EDSS score of at least 6. B and D, Survival plots derived from the multivariable Cox proportional hazard models (adjusted for EDSS evaluations per year, period of EDSS assessment, disease duration at first EDSS evaluation, age at onset, sex, annualized relapse rate in the first 3 years, type of clinical onset, and time from onset to diagnosis) with hazard ratios (HR) and relative 95% CI. Diagnosis epoch before 1993 was taken as reference.
Figure 3.
Figure 3.. Clinical Disease Activity at Onset, Time to Diagnosis, and Disease-Modifying Therapy (DMT) Management Compared by Diagnosis Epochs
Annualized relapse rate is expressed as means, number of patients treated as percentage, and all the other variables as medians, including the proportion of time spent taking DMT treatment ([total time taking DMTs/disease duration at last follow-up] × 100). For all the variables reported in the figure, statistical tests used to evaluate the variation among the 4 diagnosis epochs (χ2, analysis of variance, or Kruskal-Wallis test) gave significant results, with P values less than .001. Post hoc tests for multiple comparisons (6 for each variable: χ2, Mann-Whitney, or t test, all corrected by Bonferroni) were all significant (P < .05), except for the comparisons reported as not significant in A and B. aExpanded Disability Status Scale (EDSS) score evaluated ±6 months from diagnosis; data available on 70 patients (<1993), 261 patients (1993-1999), 473 patients (2000-2006), and 538 patients (2007-2013). bEDSS score evaluated ±3 months from DMT initiation; data available on 244 patients (<1993), 383 patients (1993-1999), 551 patients (2000-2006). and 550 patients (2007-2013).
Figure 4.
Figure 4.. Changes in Specific Disease-Modifying Therapy (DMT) Management Among Diagnosis Epochs
A, Median times to start DMTs from onset. Dotted lines indicate rarely used therapies (<5% of patients treated). Generally, time to start DMTs significantly decreased over time (P < .001; Kruskal-Wallis test), except for bone marrow transplant (BMT) (P = .85) and for low-potency immunosuppressors (IS) (P = .58). B, Percentage of patients who used a specific type of DMTs, indicating the absolute number of patients above each column. The most used DMTs at all times were first-line injectables (copolymer [glatiramer acetate] [COP]/ interferon beta [IFN]), while the use of low-/high-potency IS gradually decreased over time. Second-line treatment (natalizumab [NAT] and fingolimod [FTY]) were the most used options after first-line treatments in later diagnosis epochs. Changes in the use of DMTs among diagnosis epochs were all significant (P < .05; χ2 test) except for BMT (P = .29). C, Median proportion of time spent taking DMT treatment ([total time receiving DMTs/disease duration at last follow-up] x 100). Time spent taking low-/high-potency IS, BMT, and intravenous immunoglobulin [IVG] did not change over time (P > .10; Kruskal-Wallis test), while it significantly changed for all other DMTs (P < .01). In particular, time spent receiving second-line treatment increased in recent diagnosis epochs (especially receiving NAT and FTY). Time spent taking first-line injectables (COP/IFN) gradually increased from pre-1993 to 2000 to 2006, then it decreased in 2007 to 2013, probably owing to the availability of many other DMTs. ALZ indicates alemtuzumab; CLA, cladribine; DIM, dimethyl fumarate; OCR, ocrelizumab; RTX, rituximab; TER, teriflunomide.
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