The CHORDS trial evaluated ocrelizumab (OCR) in patients with relapsing‐remitting multiple sclerosis who had a suboptimal response to previous disease‐modifying treatment. The objective of the ...present study was to assess the safety of shorter OCR infusions in a substudy of CHORDS. After completing four doses of OCR per initial US prescribing recommendations in the main study, participants in the substudy (N = 129) received a fifth dose over a 2‐h duration (vs. 3.5 h). Infusion‐related reactions occurred in 12.4% of patients. None were severe, life‐threatening or led to treatment discontinuation. Shorter infusion time did not change the safety profile of OCR. Clinicaltrials.gov (NCT0237856).
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this 96-week, placebo-controlled trial, oral cladribine reduced relapse rates and lowered the risk of sustained disability in patients with relapsing–remitting multiple sclerosis. Patients who ...were treated with cladribine had large reductions in lymphocyte counts and more infections, including herpes zoster and one death from reactivation of tuberculosis.
Oral cladribine reduced relapse rates and lowered the risk of sustained disability in patients with relapsing–remitting multiple sclerosis. Patients had large reductions in lymphocyte counts and more infections, including herpes zoster and one death from reactivation of tuberculosis.
Multiple sclerosis is a chronic and debilitating autoimmune disorder of the central nervous system, in which T and B cells are believed to play a major pathophysiological role.
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Treatment benefits and disease modification can be obtained with the currently approved parenteral immunomodulatory and immunosuppressant therapies: interferon beta, glatiramer acetate, mitoxantrone, and natalizumab. However, treatment responses are often less than complete, and concern regarding safety and side-effect profiles may limit the general use of these drugs. The need for parenteral administration may present relative or absolute barriers to access, limiting treatment adherence and long-term outcomes.
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Intracellular accumulation of the active . . .
Background:
Many patients with multiple sclerosis (MS) experience suboptimal disease control despite the use of disease-modifying therapy (DMT).
Objective:
To assess the efficacy and safety of ...ocrelizumab (OCR) in patients with relapsing-remitting MS (RRMS) and suboptimal response to prior DMTs.
Methods:
Patients with RRMS and suboptimal responses (one clinically reported relapse and/or lesion activity) after ⩾ 6 months on another DMT were enrolled. OCR 600 mg was given intravenously every 24 weeks. The primary outcome was no evidence of disease activity (NEDA), defined as the absence of protocol-defined relapse, confirmed disability progression (CDP), T1 Gd-enhancing lesions, and new/enlarging T2 lesions.
Results:
The intention-to-treat (ITT) population included 608 patients; NEDA was analyzed in a modified ITT (mITT) population (n = 576 (94.7%)). Over 96 weeks, 48.1% of mITT patients achieved NEDA, and most were free from protocol-defined relapse (89.6%), CDP (89.6%), and T1 Gd-enhancing lesions (95.5%); 59.5% had no new/enlarging T2 lesions. Safety observations were consistent with findings in the pivotal trials.
Conclusion:
Consistent efficacy of OCR on clinical and magnetic resonance imaging (MRI) disease activity measures and progression was shown in patients with RRMS and a suboptimal response to prior DMTs; no new safety signals were observed.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Background:
Upper extremity (UE) impairment is common with primary progressive multiple sclerosis (PPMS).
Objective:
This exploratory analysis examined the effects of ocrelizumab on confirmed ...progression (CP) and confirmed improvement (CI) in UE impairment in patients from ORATORIO.
Methods:
Patients with PPMS received ocrelizumab 600 mg or placebo every 24 weeks for ⩾120 weeks. The Nine-Hole Peg Test (9HPT) was administered at baseline (BL) and every 12 weeks thereafter. Prespecified exploratory endpoints included change in 9HPT time and proportion of patients with CP of ⩾20% in 9HPT. Analysis populations included intention-to-treat (ITT) patients and subgroups stratified by BL 9HPT time and Expanded Disability Status Scale. Post hoc analyses included the proportion of patients achieving more severe thresholds of CP and the proportion achieving CI in 9HPT.
Results:
Among ITT patients, ocrelizumab significantly reduced the change in 9HPT time over 120 weeks, the risk of CP of ⩾20% in 9HPT time for both hands and the risk of more severe 9HPT progression versus placebo. Numerical trends also favoured ocrelizumab versus placebo with respect to achieving CI. Consistent directional trends were observed in subgroup analyses.
Conclusion:
Ocrelizumab reduces the risk of UE disability progression and may increase the possibility of improvement versus placebo in PPMS.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper ...depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20
CD8
T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20
CD8
T cells had a greater contribution to treatment-associated changes in the CD8
T cell pool than was the case for CD4
T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20
CD8
T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19
CD24
CD38
with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20
CD8
T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8
T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.
IMPORTANCE: Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that ...most closely reflects central nervous system biology. OBJECTIVE: To identify CSF biological measures associated with progressive MS pathobiology. DESIGN, SETTING, AND PARTICIPANTS: This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). EXPOSURES: Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. MAIN OUTCOMES AND MEASURES: Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions SELs). RESULTS: The test cohort (n = 131) included 100 patients with RMS (mean SD age, 36.6 10.4 years; 68 68% female and 32 32% male; Expanded Disability Status Scale EDSS score, 0-5.5), and 31 patients with PPMS (mean SD age, 44.9 7.4 years; 15 48% female and 16 52% male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years range, 20-61 years; 47 69% female and 21 31% male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = –0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = –0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). CONCLUSIONS AND RELEVANCE: In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.
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