BACKGROUND: Cognitive impairment is a well-recognized symptom of multiple sclerosis (MS) that can manifest early in the disease course. Deficits in cognitive function can have a major impact on daily life. However, cognitive decline is often under-examined in clinical trials and clinical practice due to lack of adequate data. The objective of this study was to examine the longitudinal effect of ocrelizumab vs interferon beta (IFNβ)-1a on cognitive impairment in 2 phase 3 studies in relapsing MS (RMS). METHODS: The pooled population of participants with RMS (n = 1656) from the OPERA I/II clinical trials received subcutaneous IFNβ-1a (44 μg; n = 829) 3 times weekly or intravenous ocrelizumab (600 mg; n = 827) every 24 weeks. Cognition was assessed with a Symbol Digit Modalities Test (SDMT), administered in written or oral form according to each site investigator's choice, that primarily measured cognitive processing speed at baseline and every 12 weeks until the end of the double-blind treatment (96 weeks). Treatment effects were investigated based on longitudinal linear models for the change from baseline in SDMT and Cox regression for the time to 12- or 24-week confirmed decline of ≥4 points. RESULTS: Among the participants with an SDMT assessment at baseline and ≥1 postbaseline time point (IFNβ-1a, n = 749; ocrelizumab, n = 766), ocrelizumab treatment was associated with a greater mean SDMT improvement over 96 weeks than IFNβ-1a treatment (5.4 [95 % CI, 4.4-6.5] vs 4.0 [95 % CI, 3.0-5.1]; adjusted mean difference, 1.4 [95 % CI, 0.05-2.72]; P = 0.042). The risk of a clinically meaningful SDMT decline (≥4 points) was lower for those treated with ocrelizumab for both ≥12 weeks (IFNβ-1a, 18.4 %; ocrelizumab, 12.7 %; hazard ratio, 0.63 [95 % CI, 0.47-0.85]; P = 0.003) and ≥24 weeks (IFNβ-1a, 12.9 %; ocrelizumab, 7.9 %; HR, 0.57 [95 % CI, 0.39-0.82]; P = 0.003). CONCLUSION: Ocrelizumab treatment resulted in better cognitive outcomes as measured by SDMT in participants with RMS compared with IFNβ-1a treatment. However, methodological limitations need to be considered when interpreting these data. CLINICALTRIALS: gov: NCT01247324, NCT01412333.
- MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Antibodies, Monoclonal, Humanized * administration & dosage pharmacology adverse effects MeSH
- Immunologic Factors * administration & dosage adverse effects pharmacology MeSH
- Interferon beta-1a * administration & dosage pharmacology MeSH
- Cognitive Dysfunction etiology drug therapy chemically induced MeSH
- Middle Aged MeSH
- Humans MeSH
- Longitudinal Studies MeSH
- Multiple Sclerosis, Relapsing-Remitting * drug therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Clinical Trial, Phase III MeSH
- Randomized Controlled Trial MeSH
- Comparative Study MeSH
BACKGROUND AND OBJECTIVES: Patients with multiple sclerosis (MS) may demonstrate better disease control when treatment is initiated on high-efficacy disease-modifying therapies (DMTs) from onset. This subgroup analysis assessed the long-term efficacy and safety profile of the high-efficacy DMT ocrelizumab (OCR) as first-line therapy for early-stage relapsing MS (RMS). METHODS: Post hoc exploratory analyses of efficacy and safety were performed in a subgroup of treatment-naive patients with RMS who received ≥1 dose of OCR in the multicenter OPERA I/II (NCT01247324/NCT01412333) studies. Patients were randomized to OCR or interferon β-1a for 96 weeks (double-blind controlled treatment period [DBP]), before switching to OCR in the open-label extension (OLE). Efficacy assessments included no evidence of disease activity (NEDA-3), 24-week confirmed disability progression (CDP), MRI lesion activity, change in whole-brain volume; with safety outcomes assessed over a 9-year treatment period. RESULTS: Overall, 757 patients were included (interferon-treated n = 382, mean age 36.3 years, 65.7% female; OCR-treated n = 375, mean age 35.5 years, 64.0% female); 505 of 757 (66.7%) completed 9 years of follow-up. The difference in NEDA status between OCR-treated and interferon-treated patients achieved during the DBP (72.5% and 43.8%, respectively, odds ratio 3.48, 95% CI 2.52-4.81) was maintained throughout the 7-year OLE (48.2% vs 25.7%; odds ratio 2.72, 95% CI 1.94-3.82). No 24-week CDP was observed in 78.7% of OCR-treated patients over 9 years. Brain volume loss over the entire study period remained numerically higher among patients starting OCR later (p = 0.09 at OLE at week 336). During the DBP, safety profiles in both groups were similar; no new safety signals were observed during the OLE. Over >9 years of continuous OCR treatment, the rate of infections remained low and stable over time. DISCUSSION: A higher proportion of OCR-treated patients achieved NEDA status compared with interferon-treated patients during the DBP, which was maintained throughout the OLE. After switching to OCR, disability accrual and brain volume loss among interferon-treated patients became similar to the OCR-OCR group, but disability and brain volume loss accrued during interferon treatment were not recovered. Possible study limitations include assessment bias due to unmaintained blinding during the OLE. These data support OCR as first-line therapy for these patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that OCR delays disease progression in treatment-naïve patients with early-stage RMS.
- MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Antibodies, Monoclonal, Humanized * adverse effects therapeutic use administration & dosage MeSH
- Immunologic Factors * adverse effects administration & dosage therapeutic use MeSH
- Interferon beta-1a therapeutic use administration & dosage MeSH
- Middle Aged MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Disease Progression MeSH
- Multiple Sclerosis, Relapsing-Remitting * drug therapy diagnostic imaging MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
Tato kazuistika popisuje léčbu pacienta s relabující-remitující formou roztroušené sklerózy (RR-RS), který zároveň trpí Crohnovou nemocí. Po počáteční terapii glatiramer-acetátem a interferonem beta-1a došlo u pacienta k pokračující aktivitě onemocnění, která si vyžádala změnu léčby. S ohledem na potřebu vysoce účinné terapie a pacientovu preferenci méně častých návštěv zdravotnického zařízení byla v dubnu 2022 zahájena léčba ponesimodem. Po více než dvouleté léčbě pacient zůstává klinicky stabilní, bez nových atak či progrese nemoci, a Crohnova nemoc je v remisi. Pacient dobře toleruje léčbu a vede plnohodnotný život, což potvrzuje účinnost a bezpečnost ponesimodu jako vhodné volby pro pacienty s aktivní RS a komorbiditami.
This case report describes the treatment of a patient with relapsing-remitting multiple sclerosis (RR-RS) who also suffers from Crohn's disease. After initial therapy with glatiramer acetate and interferon beta-1a, the patient had ongoing disease activity that required a change in treatment. Considering the need for highly effective therapy and the patient's preference for less frequent visits to the medical facility, treatment with ponesimod was started in April 2022. After more than two years of treatment, the patient remains clinically stable, without new relapses or disease progression, and Crohn's disease is in remission. The patient tolerates the treatment well and leads a full life, which confirms the efficacy and safety of ponesimod as a suitable choice for patients with active MS and comorbidities.
- Keywords
- ponesimod,
- MeSH
- Crohn Disease diagnosis drug therapy MeSH
- Demyelinating Diseases diagnostic imaging MeSH
- Adult MeSH
- Quality of Life MeSH
- Humans MeSH
- Magnetic Resonance Imaging methods MeSH
- Disease Progression MeSH
- Sphingosine-1-Phosphate Receptors * antagonists & inhibitors therapeutic use MeSH
- Multiple Sclerosis, Relapsing-Remitting * diagnosis drug therapy MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
BACKGROUND: To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon β-1a (IFN) using observational data. METHODS: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression. RESULTS: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51). CONCLUSIONS: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research.
- MeSH
- Adult MeSH
- Fingolimod Hydrochloride * therapeutic use MeSH
- Immunosuppressive Agents therapeutic use MeSH
- Interferon beta-1a * therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Randomized Controlled Trials as Topic * MeSH
- Registries * MeSH
- Multiple Sclerosis, Relapsing-Remitting * drug therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease that secondarily leads to axonal loss and associated brain atrophy. Disease-modifying drugs (DMDs) have previously been studied for their ability to affect specific immunity. This study investigates the effect of interferon beta-1a (INF) and glatiramer acetate (GA) administration on changes in innate immunity cell populations. METHODS: Sixty Caucasian female patients with relapsing-remitting MS undergo blood sample testing for 15 blood parameters at baseline, 1 month, 3 months, and 6 months after treatment by GA or IFN (started as their first-line DMD). RESULTS: A statistically significant difference in the change after 6 months was found in the parameter monocytes (relative count) in the group of patients treated with IFN. The median increase was 27.8%. Changes in many of the other 15 parameters studied were 10-20%. CONCLUSION: Innate immunity has long been neglected in MS immunopathology. The findings suggest that IFN treatment may modulate the immune response in MS by affecting monocyte function and may provide insight into the mechanisms of action of IFN in MS.
- MeSH
- Glatiramer Acetate therapeutic use MeSH
- Interferon beta-1a therapeutic use MeSH
- Interferon-beta therapeutic use MeSH
- Humans MeSH
- Peptides therapeutic use MeSH
- Immunity, Innate MeSH
- Multiple Sclerosis, Relapsing-Remitting * drug therapy pathology MeSH
- Multiple Sclerosis * drug therapy MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Keywords
- siponimod,
- MeSH
- Dimethyl Fumarate therapeutic use MeSH
- Interferon beta-1a administration & dosage MeSH
- Middle Aged MeSH
- Humans MeSH
- Sphingosine 1 Phosphate Receptor Modulators * therapeutic use MeSH
- Disease Progression MeSH
- Multiple Sclerosis * diagnosis drug therapy pathology MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Alemtuzumab economics therapeutic use MeSH
- Adult MeSH
- Fingolimod Hydrochloride therapeutic use MeSH
- Adrenal Cortex Hormones therapeutic use MeSH
- Interferon beta-1a administration & dosage MeSH
- Middle Aged MeSH
- Humans MeSH
- Natalizumab * administration & dosage economics adverse effects MeSH
- Treatment Failure MeSH
- Recurrence MeSH
- Multiple Sclerosis * diagnosis drug therapy pathology therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Demyelinating Diseases drug therapy MeSH
- Interferon beta-1a therapeutic use MeSH
- Clinical Decision-Making MeSH
- Central Nervous System Agents adverse effects therapeutic use MeSH
- Humans MeSH
- Natalizumab administration & dosage MeSH
- Drug-Related Side Effects and Adverse Reactions epidemiology MeSH
- Multiple Sclerosis * drug therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
OBJECTIVE: To compare the effectiveness of glatiramer acetate (GA) vs intramuscular interferon beta-1a (IFN-β-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments. METHODS: Data from 2 independent multiple sclerosis datasets, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating GA vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors. RESULTS: The overall ARR ratio of GA to IFN-β-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration, and Expanded Disability Status Scale score) detected differential response of GA vs IFN-β-1a: in the trial, patients with the largest benefit from GA vs IFN-β-1a (lower score quartile) had an ARR ratio of 0.40 (95% confidence interval [CI] 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI 0.61-1.34), and those in the upper quartile of 1.14 (95% CI 0.59-2.18) (heterogeneity p = 0.012); this result was validated on MSBase, with the corresponding ARR ratios of 0.58 (95% CI 0.46-0.72), 0.92 (95% CI 0.77-1.09,) and 1.29 (95% CI 0.97-1.71); heterogeneity p < 0.0001). CONCLUSIONS: We demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFN-β-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice.
- MeSH
- Adjuvants, Immunologic administration & dosage MeSH
- Databases, Factual trends MeSH
- Adult MeSH
- Glatiramer Acetate administration & dosage MeSH
- Immunosuppressive Agents administration & dosage MeSH
- Injections, Intramuscular MeSH
- Interferon beta-1a administration & dosage MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiple Sclerosis, Relapsing-Remitting diagnosis drug therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Observational Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Research Support, N.I.H., Extramural MeSH
