Ocrelizumab in Patients with Active Primary Progressive Multiple Sclerosis: Clinical Outcomes and Immune Markers of Treatment Response
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Study Procedures
2.3. B-Cell Immunophenotype
2.4. Serum Cytokine Profile
2.5. Clinical, MRI and Laboratory Outcomes
2.5.1. Primary Outcome
2.5.2. Secondary Outcomes
- The proportion of patients with optimal response at 12 months. Optimal response is defined as absence of relapses, absence of new/enlarged T2 lesions on the brain and cervical MRI and absence of CDA, defined as 1 point of EDSS increase (0.5 point if baseline EDSS ≥ 5.5, confirmed after 6 months from the previous last evaluation) at 12 and at 24 months.
- The mean time to optimal response for patients who exhibited optimal response at 24 months. As per study design, patients were evaluated every 6 months.
- The proportion of patients with CDA defined as 1 point of EDSS increase (0.5 point if baseline EDSS ≥ 5.5), at 12 and at 24 months, relative to the last previous evaluation time point.
- The proportion of patients with MRI activity at 12 and 24 months (defined as the presence of new/enlarged T2 lesions with respect to previous brain MRI.
2.5.3. Exploratory Outcomes
- Mean change in EDSS from baseline at 12- and 24-month point estimates (for all patients and for responders vs. non-responders at 24 months).
- Mean change in total number of new and/or enlarged T2 lesions at 12- and 24-month point estimates (for all patients and for responders vs. non-responders at 24 months).
- Mean change in cognitive performance scales’ scores, namely, BICAMS (including SDMT, GVLT, BVMT-R), for the assessment of processing speed, verbal and visuospatial memory, respectively, from baseline at 12- and 24-month point estimates (for all patients and for responders vs. non-responders at 24 months).
- Mean change in volumetric parameters in cm3 and in percentage of total brain volume from baseline at 12- and 24-month point estimates (for all patients and for responders vs. non-responders at 24 months). Example measurements include, but are not restricted to, overall, cerebrum and cerebellar white and gray matter, brainstem and areas of subcortical gray matter.
- Mean change in lesion (white matter) analysis parameters, namely, lesion count, lesion volume in cm3 and normalized lesion volume, as well as overall lesion burden, from baseline at 12- and 24-month point estimates (for all patients and for responders vs. non-responders at 24 months).
- Possible association between mean EDSS score and/or mean cognitive scores and MRI volumetry and/or lesion analysis at 12- and 24-month point estimates.
- Mean change in B-cell subtypes from baseline at 6-, 12-, 18- and 24-month point estimates (for all patients and for responders vs. non-responders at 24 months).
- Mean change in serum cytokine profile from baseline at 6- and 12-month point estimates (for all patients and for responders vs. non-responders at 24 months).
2.6. Statistical Analysis
3. Results
3.1. Baseline Characteristics, Safety and Treatment Withdrawal
3.2. Primary and Secondary Outcomes
3.3. Exploratory Outcomes
- Cognitive function
- MRI volumetry—association with cognitive performance
- Immune cell phenotype
- Serum cytokine analysis
4. Discussion
Limitations and Future Directions
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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All (N = 22) | Non-Responders (N = 9) | Responders (N = 13) | p * | |
---|---|---|---|---|
Gender (male/female) Age Education (years) | 12/10 | 5/4 | 7/6 | 0.937 |
48.5 ± 1.69 | 49.56 ± 3.45 | 47.77 ± 1.69 | 0.948 | |
14.05 ± 0.7 | 15.44 ± 1.16 | 13 ± 0.78 | 0.058 | |
Disease duration (years) Time from diagnosis (years) | 9.05 ± 0.92 | 8.89 ± 1.79 | 9.15 ± 1.02 | 0.556 |
5.59 ± 0.84 | 6.44 ± 1.44 | 6.69 ± 1.06 | 0.512 | |
Smoking (yes/no) Cardiovascular comorbidities ** Other (non-cardiovascular) comorbidities *** EDSS | 10/12 | 2/7 | 8/5 | 0.069 |
16/2/4 | 8/0/1 | 8/2/3 | 0.309 | |
16/6/1/1/1 | 7/2/0/0/0 | 9/4/1/1/1 | 0.556 | |
4.91 ± 0.3 | 4.56 ± 0.56 | 5.15 ± 0.34 | 0.324 | |
MRI new/enlarged T2 lesions (brain and cervical) MRI Gd+ lesions (brain and cervical) | 1.05 ± 0.26 | 0.89 ± 0.39 | 1.15 ± 0.36 | 0.647 |
0.36 ± 0.12 | 0.44 ± 0.18 | 0.31 ± 0.17 | 0.512 |
Proportion of Patients, n/N (%) 95% CI | 12 Months (N = 22) | 24 Months (N = 22) |
---|---|---|
Responders | 14/22 (63.6%) 0.41–0.83 | 13/22 (59.1%) 0.36–0.79 |
No CDA | 14/22 (63.6%) 0.41–0.83 | 13/22 (59.1%) 0.36–0.79 |
No new/enlarged T2 lesions (brain and cervical MRI) | 20/22 (90.9%) 0.71–0.99 | 20/22 (90.9%) 0.71–0.99 |
All (N = 22) | Non-Responders (N = 9) | Responders (N = 13) | p * | |
---|---|---|---|---|
SDMT | ||||
baseline | 42.09 ± 2.4 | 47.11 ± 3.21 | 38.62 ± 3.14 | 0.096 |
12 months | 39.91 ± 2.21 | 45 ± 3.37 | 36.38 ± 2.6 | 0.06 |
24 months | 41.59 ± 2.25 | 46.67 ± 3.18 | 38.08 ± 2.79 | 0.071 |
change from baseline (12 months) | −2.18 ± 0.89 | −2.11 ± 1.45 | −2.23 ± 1.17 | 0.061 |
change from baseline (24 months) | −5 ± 1.28 | −0.44 ± 1.45 | −0.54 ± 1.96 | 0.253 |
GVLT | ||||
baseline | 52.82 ± 2.33 | 53.56 ± 3.2 | 52.31 ± 3.37 | 0.556 |
12 months | 54.91 ± 2.52 | 58.11 ± 3.73 | 52.69 ± 3.37 | 0.324 |
24 months | 55.73 ± 2.43 | 60.33 ± 3.34 | 52.54 ± 3.2 | 0.096 |
change from baseline (12 months) | 2.09 ± 2.09 | 4.56 ± 3.04 | 0.38 ± 2.83 | 0.058 |
change from baseline (24 months) | 2.91 ± 2.43 | 6.78 ± 2.81 | 0.23 ± 3.53 | 0.288 |
BVMT-R | ||||
baseline | 19.14 ± 1.7 | 20.89 ± 1.94 | 17.92 ± 2.56 | 0.647 |
12 months | 20.41 ± 1.95 | 22.56 ± 2.87 | 18.92 ± 2.64 | 0.357 |
24 months | 18.45 ± 1.78 | 21.89 ± 2.55 | 16.08 ± 2.29 | 0.126 |
change from baseline (12 months) | 1.27 ± 1.57 | 1.67 ± 2.67 | 1 ± 2 | 0.338 |
change from baseline (24 months) | −0.68 ± 1.64 | 1 ± 2.44 | −1.85 ± 2.22 | 0.165 |
MFIS | ||||
baseline | 36.32 ± 3.2 | 30.22 ± 3.94 | 40.54 ± 4.42 | 0.082 |
12 months | 37.95 ± 3.86 | 33.89 ± 7.15 | 40.77 ± 4.34 | 0.512 |
24 months | 41.55 ± 3.64 | 36.11 ± 6.09 | 45.31 ± 4.4 | 0.235 |
change from baseline (12 months) | 1.64 ± 3.56 | 3.67 ± 7.17 | 0.23 ± 3.66 | 0.173 |
change from baseline (24 months) | 5.23 ± 3.07 | 5.89 ± 5.96 | 4.77 ± 3.38 | 0.12 |
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Boziki, M.; Bakirtzis, C.; Sintila, S.-A.; Kesidou, E.; Gounari, E.; Ioakimidou, A.; Tsavdaridou, V.; Skoura, L.; Fylaktou, A.; Nikolaidou, V.; et al. Ocrelizumab in Patients with Active Primary Progressive Multiple Sclerosis: Clinical Outcomes and Immune Markers of Treatment Response. Cells 2022, 11, 1959. https://doi.org/10.3390/cells11121959
Boziki M, Bakirtzis C, Sintila S-A, Kesidou E, Gounari E, Ioakimidou A, Tsavdaridou V, Skoura L, Fylaktou A, Nikolaidou V, et al. Ocrelizumab in Patients with Active Primary Progressive Multiple Sclerosis: Clinical Outcomes and Immune Markers of Treatment Response. Cells. 2022; 11(12):1959. https://doi.org/10.3390/cells11121959
Chicago/Turabian StyleBoziki, Marina, Christos Bakirtzis, Styliani-Aggeliki Sintila, Evangelia Kesidou, Evdoxia Gounari, Aliki Ioakimidou, Vasiliki Tsavdaridou, Lemonia Skoura, Asimina Fylaktou, Vasiliki Nikolaidou, and et al. 2022. "Ocrelizumab in Patients with Active Primary Progressive Multiple Sclerosis: Clinical Outcomes and Immune Markers of Treatment Response" Cells 11, no. 12: 1959. https://doi.org/10.3390/cells11121959