Longitudinal study of immunity to SARS-CoV2 in ocrelizumab-treated MS patients up to 2 years after COVID-19 vaccination.

OBJECTIVES: (1) To plot the trajectory of humoral and cellular immune responses to the primary (two-dose) COVID-19 mRNA series and the third/booster dose in B-cell-depleted multiple sclerosis (MS) patients up to 2 years post-vaccination; (2) to identify predictors of immune responses to vaccination; and (3) to assess the impact of intercurrent COVID-19 infections on SARS CoV-2-specific immunity. METHODS: Sixty ocrelizumab-treated MS patients were enrolled from NYU (New York) and University of Colorado (Anschutz) MS Centers. Samples were collected pre-vaccination, and then 4, 12, 24, and 48 weeks post-primary series, and 4, 12, 24, and 48 weeks post-booster. Binding anti-Spike antibody responses were assessed with multiplex bead-based immunoassay (MBI) and electrochemiluminescence (Elecsys®, Roche Diagnostics), and neutralizing antibody responses with live-virus immunofluorescence-based microneutralization assay. Spike-specific cellular responses were assessed with IFNγ/IL-2 ELISpot (Invitrogen) and, in a subset, by sequencing complementarity determining regions (CDR)-3 within T-cell receptors (Adaptive Biotechnologies). A linear mixed-effect model was used to compare antibody and cytokine levels across time points. Multivariate analyses identified predictors of immune responses. RESULTS: The primary vaccination induced an 11- to 208-fold increase in binding and neutralizing antibody levels and a 3- to 4-fold increase in IFNγ/IL-2 responses, followed by a modest decline in antibody but not cytokine responses. Booster dose induced a further 3- to 5-fold increase in binding antibodies and 4- to 5-fold increase in IFNγ/IL-2, which were maintained for up to 1 year. Infections had a variable impact on immunity. INTERPRETATION: Humoral and cellular benefits of COVID-19 vaccination in B-cell-depleted MS patients were sustained for up to 2 years when booster doses were administered.

Evolution of atrophied T2 lesion volume in primary-progressive multiple sclerosis: results from the phase 3 ORATORIO study.

BACKGROUND: Atrophied T2-lesion volume (aT2-LV) is an exploratory imaging marker in multiple sclerosis (MS) reflecting the volume of lesions subsumed into cerebrospinal fluid (CSF). OBJECTIVE: To investigate the effect of ocrelizumab (OCR) versus placebo (PBO) over 120 weeks on the accumulation of aT2-LV in a double-blind placebo-controlled (DBP) phase 3, primary-progressive (PP) MS study (ORATORIO; NCT01194570). METHODS: This post-hoc, MRI-blinded analysis evaluated 732 PPMS randomised to OCR (488) or PBO (244). Atrophied T2-LV was calculated by overlaying baseline T2-lesion masks on follow-up CSF maps. Clinical data from DBP and open-label extension (OLE) periods were available. Treatment effect was evaluated by a mixed-effect model with repeated measures, while logistic regression explored the association of aT2-LV at week 120 and clinical outcomes in the OLE period. RESULTS: OCR treatment significantly reduced accumulation of aT2-LV compared with PBO (319.4 mm3 vs 366.1 mm3, p=0.015) at 120 weeks. OCR showed superiority over PBO in reducing aT2-LV in patients who developed confirmed disability progression (CDP) during the DBP period at 12 (CDP12) and 24 (CDP24) weeks for the composite of Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test and Timed 25-Foot Walk test. Accumulation of aT2-LV at week 120 was related to CDP12-EDSS (p=0.018) and CDP24-EDSS (p=0.022) in the OLE for the patients who were treated by PBO in the DBP only. CONCLUSIONS: OCR showed a significant effect of reducing the accumulation of aT2-LV in PPMS in the DBP period and was related to CDP-EDSS in OLE only in the PBO arm.

Demographics and baseline disease characteristics of Black and Hispanic patients with multiple sclerosis in the open-label, single-arm, multicenter, phase IV CHIMES trial.

BACKGROUND: Black/African American patients with multiple sclerosis (BpwMS) and Hispanic/Latino patients with multiple sclerosis (HpwMS), who historically have been underrepresented in multiple sclerosis (MS) clinical trials, exhibit greater disease severity and more rapid disease progression than White patients with MS (WpwMS). The lack of diversity and inclusion in clinical trials, which may be due to barriers at the system, patient and study levels, impacts the ability to effectively assess risks, benefits and treatment responses in a generalized patient population. METHODS: CHIMES (Characterization of Ocrelizumab in Minorities With Multiple Sclerosis), an open-label, single-arm, multicenter, phase IV study of self-identified BpwMS and HpwMS aged 18-65 years with relapsing MS and an Expanded Disability Status Score (EDSS) of ≤5.5, was developed in collaboration with patients with MS, national advocacy groups and clinical researchers. Patients were enrolled at study centers across the US, including Puerto Rico, and 1 site in Kenya. RESULTS: A total of 182 patients enrolled in CHIMES: 113 (62.1%) were BpwMS, and 69 (37.9%) were HpwMS; the mean (SD) baseline EDSS score was 2.4 (1.4), and 62.6% of patients were treatment naive. Using the pooled non-BpwMS/HpwMS group in the OPERA ocrelizumab trials as a reference population, patients enrolled in CHIMES were younger, had a higher mean body mass and had a greater T2 lesion volume but similar T2 lesion number on MRI. CONCLUSION: BpwMS and HpwMS have been consistently underrepresented in clinical trials, limiting the understanding of disease biology and response to treatment in this population. Data from the CHIMES study revealed differences in demographics and some baseline disease characteristics and disease burden between BpwMS and HpwMS vs WpwMS. These differences could have an impact when assessing clinical outcomes in BpwMS and HpwMS. GOV IDENTIFIER: NCT04377555.

Safety and patient experience with at-home infusion of ocrelizumab for multiple sclerosis.

OBJECTIVE: This study aimed to evaluate safety (infusion-related reactions [IRRs]) and patient satisfaction (patient-reported outcomes [PROs]) for at-home ocrelizumab administration for patients with multiple sclerosis (MS). METHODS: This open-label study included adult patients with an MS diagnosis who had completed a ≥ 600-mg ocrelizumab dose, had a patient-determined disease steps score of 0 to 6 and had completed PROs. Eligible patients received a 600-mg ocrelizumab home-based infusion over 2 h, followed by 24-h and 2-week post-infusion follow-up calls. IRRs and adverse events (AEs) were documented during infusions and follow-up calls. PROs were completed before and 2 weeks post infusion. RESULTS: Overall, 99 of 100 expected patients were included (mean [SD] age, 42.3 [7.7] years; 72.7% female; 91.9% White). The mean (SD) infusion time was 2.5 (0.6) hours, and 75.8% of patients completed their ocrelizumab infusion between 2 to 2.5 h. The IRR incidence rate was 25.3% (95% CI: 16.7%, 33.8%)-similar to other shorter ocrelizumab infusion studies-and all AEs were mild/moderate. In total, 66.7% of patients experienced AEs, including itch, fatigue, and grogginess. Patients reported significantly increased satisfaction with the at-home infusion process and confidence in the care provided. Patients also reported a significant preference for at-home infusion compared with prior infusion center experiences. INTERPRETATION: IRRs and AEs occurred at acceptable rates during in-home infusions of ocrelizumab over a shorter infusion time. Patients reported increased confidence and comfort with the home infusion process. Findings from this study provide evidence of the safety and feasibility of home-based ocrelizumab infusion over a shorter infusion period.

Hybrid and vaccine-induced immunity against SAR-CoV-2 in MS patients on different disease-modifying therapies.

OBJECTIVE: To compare "hybrid immunity" (prior COVID-19 infection plus vaccination) and post-vaccination immunity to SARS CoV-2 in MS patients on different disease-modifying therapies (DMTs) and to assess the impact of vaccine product and race/ethnicity on post-vaccination immune responses. METHODS: Consecutive MS patients from NYU MS Care Center (New York, NY), aged 18-60, who completed primary COVID-19 vaccination series ≥6 weeks previously were evaluated for SARS CoV-2-specific antibody responses with electro-chemiluminescence and multiepitope bead-based immunoassays and, in a subset, live virus immunofluorescence-based microneutralization assay. SARS CoV-2-specific cellular responses were assessed with cellular stimulation TruCulture IFNγ and IL-2 assay and, in a subset, with IFNγ and IL-2 ELISpot assays. Multivariate analyses examined associations between immunologic responses and prior COVID-19 infection while controlling for age, sex, DMT at vaccination, time-to-vaccine, and vaccine product. RESULTS: Between 6/01/2021 and 11/11/2021, 370 MS patients were recruited (mean age 40.6 years; 76% female; 53% non-White; 22% with prior infection; common DMT classes: ocrelizumab 40%; natalizumab 15%, sphingosine-1-phosphate receptor modulators 13%; and no DMT 8%). Vaccine-to-collection time was 18.7 (±7.7) weeks and 95% of patients received mRNA vaccines. In multivariate analyses, patients with laboratory-confirmed prior COVID-19 infection had significantly increased antibody and cellular post-vaccination responses compared to those without prior infection. Vaccine product and DMT class were independent predictors of antibody and cellular responses, while race/ethnicity was not. INTERPRETATION: Prior COVID-19 infection is associated with enhanced antibody and cellular post-vaccine responses independent of DMT class and vaccine type. There were no differences in immune responses across race/ethnic groups.

The CELLO trial: Protocol of a planned phase 4 study to assess the efficacy of Ocrelizumab in patients with radiologically isolated syndrome.

BACKGROUND: Patients with radiologically isolated syndrome (RIS) exhibit CNS lesions suggestive of multiple sclerosis (MS) in the absence of overt neurological symptoms characteristic of the disease. They may have concurrent brain atrophy, subtle cognitive impairment, and intrathecal inflammation. At least half ultimately develop MS, cementing RIS as preclinical MS for many. However, high-quality data, including immunologic biomarkers, to guide treatment decisions in this population are lacking. Early intervention with ocrelizumab, a humanized monoclonal antibody approved for relapsing and primary progressive MS that targets CD20+ B-cells, may affect disease course and improve long-term outcomes. The objective of this study is to describe the protocol for CELLO, a clinical trial assessing the effect of ocrelizumab on RIS. METHODS: The CELLO clinical trial, a phase 4, multicenter, randomized, double-blind, placebo-controlled study conducted as an academic-industry collaboration, aims to (1) assess the efficacy of ocrelizumab in patients with RIS and (2) identify biomarkers indicative of emerging autoimmunity as well as immune recovery after transient B-cell depletion. The study will enroll 100 participants across ≥15 sites. Participants will be aged 18 to 40 years, have RIS (defined as meeting 2017 revised McDonald criteria for dissemination in space), and have either been diagnosed with RIS within the last 5 years or have had new brain lesions identified within 5 years of study entry. A screening program of first-degree relatives of patients with MS will be used to boost recruitment. Eligible patients will be randomized 1:1 to receive 3 courses of ocrelizumab or placebo at baseline, week 24, and week 48. Patients will subsequently be followed up for ≥3 years. The primary outcome is time to development of new radiological or clinical evidence of MS. Secondary and exploratory objectives will investigate neuroimaging, serological and immunologic biomarkers, cognitive function, and patient-reported outcomes. A substudy using single-cell RNA sequencing to characterize blood and CSF immune cells will assess markers associated with conversion to clinical MS. CONCLUSION: The CELLO study will improve the understanding of B-cell biology in early MS disease pathophysiology, characterize the emergence of CNS autoimmunity, and provide evidence to inform treatment decision-making for individuals with RIS. CLINICALTRIALS: GOV: NCT04877457.

Cellular and Humoral Immunity to SARS-CoV-2 Infection in Multiple Sclerosis Patients on Ocrelizumab and Other Disease-Modifying Therapies: A Multi-Ethnic Observational Study.

OBJECTIVE: The objective of this study was to determine the impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. METHODS: Patients with MS aged 18 to 60 years were evaluated for anti-nucleocapsid and anti-Spike receptor-binding domain (RBD) antibody with electro-chemiluminescence immunoassay; antibody responses to Spike protein, RBD, N-terminal domain with multiepitope bead-based immunoassays (MBI); live virus immunofluorescence-based microneutralization assay; T-cell responses to SARS-CoV-2 Spike using TruCulture enzyme-linked immunosorbent assay (ELISA); and IL-2 and IFNγ ELISpot assays. Assay results were compared by DMT class. Spearman correlation and multivariate analyses were performed to examine associations between immunologic responses and infection severity. RESULTS: Between January 6, 2021, and July 21, 2021, 389 patients with MS were recruited (mean age 40.3 years; 74% women; 62% non-White). Most common DMTs were ocrelizumab (OCR)-40%; natalizumab -17%, Sphingosine 1-phosphate receptor (S1P) modulators -12%; and 15% untreated. One hundred seventy-seven patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, and 47 were asymptomatic. Antibody responses were markedly attenuated in OCR compared with other groups (p ≤0.0001). T-cell responses (IFNγ) were decreased in S1P (p = 0.03), increased in natalizumab (p <0.001), and similar in other DMTs, including OCR. Cellular and humoral responses were moderately correlated in both OCR (r = 0.45, p = 0.0002) and non-OCR (r = 0.64, p <0.0001). Immune responses did not differ by race/ethnicity. Coronavirus disease 2019 (COVID-19) clinical course was mostly non-severe and similar across DMTs; 7% (9/130) were hospitalized. INTERPRETATION: DMTs had differential effects on humoral and cellular immune responses to SARS-CoV-2 infection. Immune responses did not correlate with COVID-19 clinical severity in this relatively young and nondisabled group of patients with MS. ANN NEUROL 2022;91:782-795.

Efficacy and safety of ocrelizumab vs interferon beta-1a in participants of African descent with relapsing multiple sclerosis in the Phase III OPERA I and OPERA II studies.

BACKGROUND: People of African descent with multiple sclerosis (MS) appear to have a more severe disease course and may have an attenuated response to some medications compared with people of European descent. METHODS: This is a post hoc subgroup analysis of participants of African descent with relapsing forms of MS who were enrolled in the Phase III OPERA I or OPERA II clinical trials and treated with ocrelizumab (OCR) 600 mg every 6 months or interferon beta-1a (IFN ß-1a) 44 µg 3 times per week. RESULTS: Among the 1,656 participants enrolled in OPERA I and II, 72 (4.3%) were of African descent (OCR, 40; IFN ß-1a, 32). A trend for reduction in annualized relapse rate (ARR) was observed in participants of African descent, with an ≈50% reduction with OCR vs IFN ß-1a. The relative rate of the mean number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) was 0.04 (95% CI, 0.01-0.22; p=0.001) in participants of African descent treated with OCR compared with IFN ß-1a. Similarly, the relative rate of the number of new or enlarging T2 lesions on MRI was 0.14 (95% CI, 0.06-0.32; p<0.001). In participants of African descent, those treated with OCR were 2.61 times more likely than those who received IFN ß-1a to be classified as having no evidence of disease activity (95% CI, 1.24-5.49; p=0.003) and 4.17 times more likely to be classified as having no evidence of disease activity or progression (95% CI, 1.27-13.65; p=0.006). African-descent participants tended to have a greater radiographic burden of disease at baseline, develop more brain lesions when treated with IFN ß-1a, and be at greater risk of disability progression than non-African-descent participants. Participants of African descent experienced slightly more adverse events, serious adverse events, and hypersensitivity reactions than non-African-descent participants. CONCLUSION: In this small sample of participants of African descent with relapsing MS from the OPERA studies, OCR demonstrated treatment benefits in clinical, MRI, and composite efficacy outcomes vs IFN ß-1a, consistent with what was observed in the complete OPERA intention-to-treat cohorts.

Clinical outcomes of patients with giant cell arteritis treated with tocilizumab in real-world clinical practice: decreased incidence of new visual manifestations.

BACKGROUND: Placebo-controlled clinical trials have demonstrated the efficacy of tocilizumab (TCZ) for remission maintenance and glucocorticoid sparing in patients with giant cell arteritis (GCA). However, limited data exist on the effectiveness and safety of TCZ for GCA in real-world clinical practice. METHODS: This was a retrospective, single-center analysis of patients with GCA treated with intravenous or subcutaneous TCZ (2010-2018). Outcomes evaluated before and after TCZ initiation included occurrence of flare, time to flare, annualized flare rate, flare characteristics (i.e., polymyalgia rheumatica [PMR] symptoms, cranial manifestations), prednisone use, and safety. Flare was defined as the recurrence of unequivocal GCA manifestations requiring treatment intensification. Subgroup analyses of patients with PMR or visual manifestations at GCA diagnosis were performed. RESULTS: Sixty patients with GCA were included. The median (IQR) disease duration before and after the start of TCZ was 0.6 (0.2-1.6) and 0.5 (0.3-1.4) years, respectively. At least 1 flare was observed in 43 patients (71.7%) before and in 18 (30.0%) after TCZ initiation. Median (IQR) time to flare was 0.5 (0.3-0.7) years before TCZ treatment and 2.1 (0.6-2.6) years after TCZ initiation (HR 0.22; 95% CI 0.10-0.50; p = 0.0003). The annualized flare rate significantly decreased following TCZ use (before TCZ 1.4 [95% CI 1.0-2.1]; after TCZ 0.6 [95% CI 0.3-1.0] events/year; p < 0.001). Similar improvements were observed in patients with visual manifestations or PMR symptoms at GCA diagnosis. TCZ reduced the incidence of new visual manifestations, and no flares associated with permanent vision loss occurred while patients were receiving TCZ. Mean (SD) prednisone dose at TCZ onset and at the end of follow-up was 30 (18.3) and 5 (6.9) mg/day, respectively (p < 0.0001). After TCZ initiation, 46.6% of patients successfully discontinued prednisone. The incidence of adverse events, primarily attributed to glucocorticoids, was similar before and after TCZ initiation. CONCLUSIONS: In this real-world setting, TCZ improved GCA clinical outcomes significantly and demonstrated effectiveness in the subgroups of patients with PMR symptoms and GCA-related visual manifestations at GCA diagnosis. No new cases of blindness occurred after TCZ initiation. Adverse events, many attributable to glucocorticoids, were comparable before and after TCZ treatment.

Safety results of administering ocrelizumab per a shorter infusion protocol in patients with primary progressive and relapsing multiple sclerosis.

BACKGROUND: Ocrelizumab is an approved MS treatment administered as two 300-mg intravenous infusions 2 weeks apart (Dose 1), each lasting approximately 2.5 hours, followed by single 600-mg infusions every 6 months lasting approximately 3.5 hours. Our objective was to evaluate shorter-duration ocrelizumab infusions in the Phase IIIb open-label SaROD study (NCT03606460). METHODS: Eligible patients received ocrelizumab 600-mg Dose 2 or 3 infused over approximately 2 hours (Cohort 1) or ocrelizumab 300-mg Dose 1, Infusion 2 over approximately 1.5 hours (Cohort 2). The primary endpoint was the number and proportion of patients experiencing Grade 3-4 infusion-related reactions (IRRs) in Cohort 1. Secondary endpoints included Grade 1-4 IRRs in both cohorts and Grade 3-4 IRRs in Cohort 2. RESULTS: Mean infusion times decreased by approximately 1.09 and 0.79 hours in Cohorts 1 and 2, respectively, compared with US prescribing information. IRRs, reported by 36% of 141 patients, were mild-to-moderate, with no observed Grade 3-4 IRRs. No IRR-related discontinuations occurred. No serious AEs, deaths, or new safety signals were observed. CONCLUSION: The IRR rate with ocrelizumab shorter-duration infusions was similar to that observed in the pivotal Phase III trials. Ocrelizumab can be infused over a shorter time without sacrificing patient safety.

An exploratory analysis of the efficacy of ocrelizumab in patients with multiple sclerosis with increased disability.

BACKGROUND: Ocrelizumab, an anti-CD20 humanized monoclonal antibody, reduced disease progression in pivotal trials of patients with relapsing (OPERA I, OPERA II) and primary progressive (ORATORIO) multiple sclerosis (MS). These effects may be particularly important among patients with increased disability. OBJECTIVE: In this post hoc exploratory analysis, we evaluated the efficacy of ocrelizumab on disability progression among a subgroup of patients with MS who had increased baseline disability levels (Expanded Disability Status Scale scores ≥4.0) in the pivotal trials. METHODS: During the double-blind period, patients received ocrelizumab 600 mg intravenously every 24 weeks for 96 weeks in the OPERA trials (versus interferon ß-1a 44 µg subcutaneously three times per week) and for 120 weeks in ORATORIO (versus placebo). Kaplan-Meier and Cox survival analyses were used to assess disability outcome measures. RESULTS: Baseline demographic, disease, and treatment characteristics were generally comparable across treatment groups in patients with increased disability from the OPERA and ORATORIO trials. Ocrelizumab treatment numerically, and in some instances significantly, reduced confirmed disability progression versus the comparator in these patients. CONCLUSIONS: In patients with increased baseline disability, ocrelizumab reduced the risk of confirmed disability progression versus interferon ß-1a in patients with relapsing-onset MS and versus placebo in patients with progression-onset MS.

Comparative Cost per Response for 4 Clinical Endpoints with Tocilizumab Monotherapy vs Adalimumab Monotherapy in a Head-to-Head Randomized Double-Blind Superiority Trial (ADACTA) in Patients with Rheumatoid Arthritis.

INTRODUCTION: The cost-effectiveness of different biologic therapies can be an important component in guiding treatment decisions for patients with rheumatoid arthritis (RA). The objective of this study was to compare drug and adverse event costs and cost per successful clinical response with tocilizumab (TCZ) monotherapy vs adalimumab (ADA) monotherapy in patients with RA in a phase 4 clinical trial. METHODS: Patients received either TCZ intravenously every 4 weeks or ADA subcutaneously every 2 weeks for 24 weeks. Drug and administration costs were based on wholesale acquisition costs and the Centers for Medicare and Medicaid, respectively. Outcomes included patient-level drug costs, cost of hospitalization due to adverse events, and cost per response. Cost per response was calculated by dividing the mean drug plus administration cost by the proportion of patients achieving Disease Activity Score in 28 joints (DAS28) < 2.6 (remission) or 20%, 50%, or 70% improvement in response per the American College of Rheumatology (ACR20/50/70). Hospitalization costs were calculated using the daily hospital cost and number of hospital days. RESULTS: Among the 163 patients treated with TCZ and 162 patients treated with ADA, mean total drug and administration costs per patient over 24 weeks were $18,290.60 and $25,623.10, respectively. Mean drug and administration costs per each clinical response achieved were lower with TCZ than with ADA (DAS28 < 2.6: $45,868 vs $244,174; ACR20: $28,127 vs $51,887; ACR50: $38,720 vs $92,244; ACR70: $56,253 vs $143,136). The total hospital days were 32 days with TCZ and 43 days with ADA; mean hospital costs per patient were $484.50 with TCZ and $651.10 with ADA. CONCLUSION: In this comparative assessment, the cost to achieve all 4 clinical endpoints was lower for patients receiving TCZ than for those receiving ADA.

Magnetic Resonance Imaging (MRI) Results Following Discontinuation of Methotrexate in Rheumatoid Arthritis Treated with Subcutaneous Tocilizumab: The COMP-ACT MRI Substudy.

OBJECTIVE: To assess differences in joint damage and inflammation using magnetic resonance imaging (MRI) between patients with rheumatoid arthritis (RA) who achieved low disease activity with tocilizumab (TCZ) + methotrexate (MTX) and subsequently continued or discontinued MTX. METHODS: In the COMP-ACT trial, US patients with RA received subcutaneous TCZ 162 mg + MTX. Those who achieved 28-joint count Disease Activity Score calculated with erythrocyte sedimentation rate (DAS28-ESR) ≤ 3.2 at Week 24 were randomized 1:1 (double-blind) to discontinue MTX (TCZ monotherapy; mono) or continue TCZ + MTX until Week 52. In a subset of patients, 1.5-Tesla MRI was used to obtain images of bilateral hands and wrists at weeks 24 and 40. Outcomes included changes in MRI-assessed synovitis, osteitis, erosion, and cartilage loss from Week 24 to Week 40, and in the proportion of patients with progression of each score. RESULTS: Of 296 patients who achieved DAS28-ESR ≤ 3.2 at Week 24, 79 were enrolled in the pilot MRI substudy and randomized to TCZ mono (n = 38) or TCZ + MTX (n = 41). Treatment with either TCZ mono or TCZ + MTX suppressed erosion progression, synovitis, osteitis, and cartilage loss. The proportion of patients with no progression in each outcome measure was similar between groups (range, TCZ mono: 84.8-97.0%; TCZ + MTX: 92.3-100%). CONCLUSION: In a subset of patients who achieved low disease activity with TCZ + MTX, MRI changes were minimal in intraarticular inflammation and damage measures in patients who discontinued MTX versus those who continued TCZ + MTX.

Adverse Events in Giant Cell Arteritis and Rheumatoid Arthritis Patient Populations: Analyses of Tocilizumab Clinical Trials and Claims Data.

INTRODUCTION: The safety profile of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) is well established. TCZ was approved to treat giant cell arteritis (GCA) in 2017 in the USA and Europe, and its safety profile in patients with GCA continues to be defined. The objective of this analysis was to examine incidence rates (IRs) of adverse events of special interest (AESI) occurring during the TCZ clinical development program and in healthcare claims data in patients with GCA or RA. METHODS: TCZ-naïve patients with GCA or RA were identified in the MarketScan administrative healthcare claims database. TCZ-treated patients with GCA from the GiACTA trial and TCZ-treated patients with RA from pooled clinical trial data were analyzed. The IRs of AESI (AESI IRs) were calculated for all cohorts. In the claims cohorts, risks of AESI were estimated using Poisson regression. RESULTS: TCZ-naïve claims cohorts comprised 4804 patients with GCA [mean (standard deviation) age 73.4 (9.8) years; follow-up 3.9 (3.1) years] and 15,164 patients with RA [age 60.3 (8.2) years; follow-up, 4.5 (2.8) years]. TCZ-treated clinical trial cohorts comprised 149 patients with GCA [age 69.5 (8.4) years; exposure approx. 138 patient-years (PY)] and 7647 with RA [age 52 (12.6) years; exposure approx. 22,394 PY]. The IRs of infections, stroke, malignancies, myocardial infarction, and gastrointestinal perforations in the GCA claims cohort exceeded those in the RA claims cohort; the risk of AESI (adjusted for age and glucocorticoid use) was higher in patients with GCA than in those with RA. Similar patterns to the claims cohorts in terms of the AESI IRs were observed in clinical trial cohorts, although the number of events was limited in the GCA trial cohort. CONCLUSION: Higher IRs of AESI were observed in patients with GCA versus those with RA in both TCZ-naïve and -treated cohorts. Differences in underlying disease, age, and glucocorticoid use may influence AESI incidence, irrespective of intervention. FUNDING: This study was funded by F. Hoffmann-La Roche Ltd and Genentech, Inc. Article processing charges were funded by F. Hoffmann-La Roche Ltd. Plain language summary is available for this article.

Ocrelizumab reduces progression of upper extremity impairment in patients with primary progressive multiple sclerosis: Findings from the phase III randomized ORATORIO trial.

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.

Long-Term Safety of Rituximab in Rheumatoid Arthritis: Analysis From the SUNSTONE Registry.

OBJECTIVE: To evaluate the long-term safety of rituximab in an observational cohort of patients with rheumatoid arthritis (RA) who had an inadequate response to ≥ 1 antitumor necrosis factor therapies in the United States (SUNSTONE Registry). METHODS: In this prospective, observational cohort study, patients received rituximab according to their physician's standard practice and were evaluated at standard-of-care follow-up visits at least every 6 months. The primary outcome was the incidence of protocol-defined significant infections. Secondary outcomes included serious adverse events potentially associated with rituximab, cardiovascular or thrombotic (CVT) events, seizures, deaths and pregnancies. Posthoc analyses assessed outcomes by concomitant medication use. RESULTS: Overall, 989 patients (safety-evaluable population) received ≥ 1 dose of rituximab, with a total follow-up of 3844 patient-years (PYs; mean duration, 3.9 years). In total, 341 significant infections occurred in 197 patients (19.9%). The incidence rates (95% CI) for significant infections, CVT events, and seizures were 8.87 (7.98, 9.86), 1.95 (1.56, 2.45), and 0.18 (0.09, 0.38) per 100 PYs, respectively. The incidence of significant infections did not increase with time or with cumulative rituximab exposure. During the study, 64 patients died (crude mortality [95% CI]: 1.66 per 100 PYs [1.30, 2.13]). The most common causes of death were infections (19 patients), malignancy (14), and cardiovascular events (13). Eight pregnancies were reported in 7 patients. CONCLUSION: In patients with RA treated with rituximab for up to 5 years, the rates of significant infections were stable over time and higher in patients who received long-term systemic steroid treatment. This article is protected by copyright. All rights reserved.

Impact of tocilizumab administered intravenously or subcutaneously on patient-reported quality-of-life outcomes in patients with rheumatoid arthritis.

OBJECTIVE: Randomised controlled trials (RCTs) have shown tocilizumab (TCZ) administered intravenously or subcutaneously with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to be superior to csDMARDs alone for improving rheumatoid arthritis (RA) disease activity. This study evaluated the effect of TCZ-intravenous and TCZ-subcutaneous on patient-reported outcomes (PROs) in three RCT populations. METHODS: OPTION (NCT00106548), BREVACTA (NCT01232569) and SUMMACTA (NCT01194414) were independent RCTs evaluating the efficacy and safety of TCZ-intravenous and/or TCZ-subcutaneous with csDMARDs in patients with RA. PROs included patient global assessment, pain, Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue and Short Form-36. Study outcomes included the proportions of patients reporting changes from baseline in PRO scores ≥ minimum clinically important differences (MCID) and scores ≥ age and gender-matched normative values. RESULTS: In OPTION, more patients who received TCZ-intravenous reported improvements in PROs ≥MCID (50%-82% vs 31%-57%) and scores ≥ normative values (16%-44% vs 5%-28%) at week 16 compared with placebo. Similarly, a greater proportion of patients in BREVACTA who received TCZ-subcutaneous reported improvements ≥ MCID (54%-73% vs 42%-55%) and scores ≥ normative values (8%-34% vs 4%-25%) at week 12 compared with placebo. In SUMMACTA, 61%-84% of patients who received TCZ-subcutaneous and 64%-84% of those who received TCZ-intravenous reported improvements ≥ MCID and 14%-41% and 15%-24%, respectively, scores ≥ normative values at week 24. CONCLUSIONS: TCZ-intravenous or TCZ-subcutaneous with csDMARDs resulted in more patients reporting clinically meaningful improvements and PRO scores ≥ normative values compared with placebo. These improvements were similar with TCZ-intravenous and TCZ-subcutaneous.

Sustained Response Following Discontinuation of Methotrexate in Patients With Rheumatoid Arthritis Treated With Subcutaneous Tocilizumab: Results From a Randomized, Controlled Trial.

OBJECTIVE: To evaluate whether tocilizumab (TCZ) monotherapy is noninferior to treatment with TCZ plus methotrexate (MTX) for maintaining clinical responses in patients with rheumatoid arthritis (RA) in whom low disease activity is achieved with TCZ plus MTX. METHODS: Patients with RA who experienced an inadequate response to MTX received MTX plus TCZ 162 mg subcutaneously. At 24 weeks, patients who achieved a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) of ≤3.2 were randomized to receive TCZ monotherapy or to continue treatment with TCZ plus MTX until week 52. The primary outcome measure was the comparison of the mean change in the DAS28-ESR from week 24 to week 40 between the TCZ monotherapy and TCZ plus MTX arms (noninferiority margin of 0.6). Secondary outcome measures included worsening of the DAS28-ESR by ≥1.2, achievement of a DAS28-ESR of <2.6 and ≤3.2, and safety and immunogenicity. RESULTS: Among the 718 patients enrolled, 296 were randomized at week 24 to receive TCZ monotherapy (n = 147) or TCZ plus MTX (n = 147). The mean changes in the DAS28-ESR from week 24 to week 40 were 0.46 and 0.14 in the TCZ monotherapy arm and the TCZ plus MTX arm, respectively (weighted difference between the groups, 0.318 [95% confidence interval 0.045, 0.592]); discontinuing MTX in TCZ responders was noninferior to continuing MTX. Safety events were broadly similar between the randomized treatment groups; the most common serious adverse event was infection, which occurred in 2.1% of patients in the TCZ monotherapy group and 2.2% of patients receiving TCZ plus MTX. CONCLUSION: Patients with RA receiving TCZ plus MTX who achieve low disease activity can discontinue MTX without significant worsening of disease activity during the 16 weeks following MTX discontinuation.

Two-year Efficacy and Safety of Subcutaneous Tocilizumab in Combination with Disease-modifying Antirheumatic Drugs Including Escalation to Weekly Dosing in Rheumatoid Arthritis.

OBJECTIVE: To evaluate the longterm efficacy and safety of subcutaneous tocilizumab (TCZ-SC) every 2 weeks (q2w) over 2 years in patients with rheumatoid arthritis who have an inadequate response to disease-modifying antirheumatic drugs (DMARD). METHODS: Patients (n = 656) were randomized 2:1 to TCZ-SC 162 mg q2w or placebo-SC q2w plus DMARD. After a 24-week double-blind period, patients (n = 457) were rerandomized to open-label TCZ-SC q2w by means of prefilled syringe or autoinjector. Escape therapy with weekly TCZ-SC was available for patients with inadequate efficacy from Week 12. Maintenance of response and safety to 2 years was assessed. Analyses used nonresponder imputation. RESULTS: The American College of Rheumatology (ACR) 20 response after TCZ-SC was maintained beyond Week 24 and was > 70% at each timepoint. ACR50/70, 28-joint Disease Activity Score remission, and ≥ 0.30 decrease from baseline in the Health Assessment Questionnaire-Disability Index response rates were also maintained after Week 24 in the TCZ-SC arm (≥ 50%, > 25%,> 32% and > 56%, respectively). Following escape for inadequate efficacy, many patients achieved ACR20 at the end of the study, 35% after escape from TCZ-SC, and 63% from placebo. The rates of serious adverse events [(11.20/100 patient-years (PY)] including serious infections (3.25/100 PY) were stable through Week 96. No association between anti-TCZ antibody development and loss of efficacy or adverse events was observed. CONCLUSION: Efficacy and safety of TCZ-SC q2w was maintained up to 2 years and remained comparable with previously published data for intravenous TCZ. Dose escalation to weekly TCZ-SC was associated with ACR responses in prior nonresponders and was well tolerated.

Impact of tocilizumab monotherapy on patient-reported outcomes in patients with rheumatoid arthritis from two randomised controlled trials.

OBJECTIVE: Two randomised controlled trials, AMBITION (NCT00109408) and ADACTA (NCT01119859), showed tocilizumab (TCZ) monotherapy superior to methotrexate (MTX) and adalimumab (ADA) monotherapy, respectively, for improving rheumatoid arthritis (RA) disease activity. This study compared the benefit of TCZ versus MTX or ADA monotherapy for improving patient-reported outcomes (PROs) in patients with RA. METHODS: PROs included patient global assessment (PtGA), pain, Health Assessment Questionnaire Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and Short Form-36 (SF-36) physical component summary (PCS) and mental component summary (MCS) and eight domain scores. Outcomes included proportions of patients reporting changes from baseline in PRO scores ≥minimum clinically important differences (MCID) and ≥age-matched and gender-matched normative values at 24 weeks. RESULTS: In AMBITION, TCZ-treated patients reported significantly greater mean improvements in HAQ (-0.7 vs -0.5), FACIT-Fatigue (8.7 vs 5.7), SF-36 PCS (9.8 vs 7.8) and five SF-36 domains at week 24 than with MTX; 45.0%-84.0% of TCZ-treated patients reported improvements ≥MCID, and 24.3%-52.1% reported scores ≥normative values across all PROs versus 39.4%-81.8% and 14.5%-45.0%, respectively, with MTX. In ADACTA, TCZ-treated patients reported significantly greater improvements in PtGA (-42.3 vs -31.8), pain (-40.1 vs -28.7), SF-36 MCS (7.9 vs 5.0) and three SF-36 domains than with ADA; 57.7%-83.3% of TCZ-treated patients reported improvements ≥MCID, and 22.1%-49.3% reported scores ≥normative values across all PROs versus 13.6%-37.8%, respectively, with ADA. CONCLUSIONS: TCZ monotherapy resulted in more patients reporting clinically meaningful PRO improvements and PRO scores ≥normative values compared with MTX or ADA monotherapy. TRIAL REGISTRATION NUMBERS: NCT00109408 and NCT01119859; Post-results.