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ObjectiveTo determine the impact of MS disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to SARS-CoV-2 infection.MethodsMS patients aged 18-60 were evaluated for anti-nucleocapsid and anti-Spike 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 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.ResultsBetween 1/6/2021 and 7/21/2021, 389 MS patients were recruited (mean age 40.3 years; 74% female; 62% non-White). Most common DMTs were ocrelizumab (OCR) - 40%; natalizumab - 17%, Sphingosine 1-phosphate receptor (S1P) modulators −12%; and 15% untreated. 177 patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, 47 - asymptomatic. Antibody responses were markedly attenuated in OCR compared to other groups (p≤ 0001). T-cell responses (IFNγ were decreased in S1P (p=0.03), increased in natalizumab (pInterpretationDMTs 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 non-disabled group of MS patients.

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 anti–tumor necrosis factor therapy in the US (SUNSTONE [Study of the Safety of Rituxan in Patients With Rheumatoid Arthritis After an Inadequate Response to Previous Anti‐TNF Therapy] 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 events, seizures, deaths, and pregnancies. Post hoc 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 3,844 patient‐years (mean duration 3.9 years). In total, 341 significant infections occurred in 197 patients (19.9%). The incidence rates (95% confidence intervals [95% CIs]) for significant infections, cardiovascular or thrombotic events, and seizures were 8.87 (95% CI 7.98–9.86), 1.95 (95% CI 1.56–2.45), and 0.18 (95% CI 0.09–0.38) per 100 patient‐years, respectively. The incidence of significant infections did not increase with time or with cumulative rituximab exposure. During the study, 64 patients died (crude mortality rate 1.66 per 100 patient‐years [95% CI 1.30–2.13]). The most common causes of death were infections (n = 19), malignancy (n = 14), and cardiovascular events (n = 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.

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.

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 CD20The 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.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.GOV: NCT04877457.

Additional file 1.

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 p 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.

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.

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.

Supplemental material, MSO911939 Supplemental Material2 for An exploratory analysis of the efficacy of ocrelizumab in patients with multiple sclerosis with increased disability by Jerry S Wolinsky Natalie J Engmann, Jinglan Pei, Ashish Pradhan Clyde Markowitz Edward J Fox in Multiple Sclerosis Journal—Experimental, Translational and Clinical

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 β-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 β-1a in patients with relapsing-onset MS and versus placebo in patients with progression-onset MS.

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)

Background Serum levels of C-X-C motif chemokine ligand 13 (CXCL13) and soluble intercellular adhesion molecule-1 (sICAM-1) have been associated with response to tocilizumab (TCZ) in patients with rheumatoid arthritis (RA); levels of matrix metalloproteinase-3 (MMP-3) and S100A8/A9 have also been associated with RA disease activity and joint damage. Objectives To evaluate the association of CXCL13, sICAM-1, MMP-3 and s100A8/A9 levels with disease activity and response to TCZ in patients with RA who achieved low disease activity with 24 weeks of TCZ + methotrexate (MTX) treatment and were subsequently randomized to TCZ monotherapy (mono) or TCZ + MTX in the COMP-ACT trial (NCT01855789). Methods US patients with RA who had an inadequate response to MTX received initial combination therapy of MTX plus TCZ 162 mg subcutaneous for 24 weeks. Patients who achieved Disease Activity Score in 28 joints calculated with erythrocyte sedimentation rate (DAS28-ESR) ≤ 3.2 at Week 24 were randomized 1:1 (double-blind) to receive either TCZ mono or continue TCZ + MTX until Week 52. Randomized patients were included in the present study based on baseline, Week 24 and Week 40 sample availability; serum levels of CXCL13, sICAM-1, MMP-3 and S100A8/A9 were measured by immunoassay. Correlations between CXCL13, sICAM-1, MMP-3 and S100A8/A9 levels and DAS28-ESR at baseline, Week 24 and Week 40 were determined according to Spearman correlation coefficient. Changes in CXCL13, sICAM-1, MMP-3 and S100A8/A9 levels from baseline to Week 24 (open-label period) were determined using Wilcoxon test. Mean changes in CXCL13, sICAM-1, MMP-3 and S100A8/A9 levels from Week 24 to Week 40 (randomized period) were compared between treatment arms using analysis of covariance. Results Of 296 randomized patients, 249 were included (TCZ mono, n = 126; TCZ + MTX, n = 123). Biomarker levels were well balanced across treatment arms at baseline and Week 24 (randomization). At baseline, there were weak to mild correlations between DAS28-ESR and biomarker levels (CXCL13 [r = 0.13, P = 0.0411], sICAM-1 [r = 0.20, P = 0.0015], MMP-3 [r = 0.19, P = 0.0021], S100A8/A9 [r = 0.25, P = 0.0001]). Significant reductions in mean biomarker levels were observed from baseline to Week 24 (open-label period) among the total randomized patients (P Conclusion In agreement with previous studies, the association between baseline disease activity and CXCL13, sICAM-1, MMP-3 and S100A8/A9 levels was weak to mild; TCZ + MTX treatment from baseline to Week 24 (open-label period) resulted in significant reductions in all biomarkers. Changes in levels of CXCL13, sICAM-1, MMP-3 and S100A8/A9 from Week 24 to 40 (randomized period) were similar between treatment groups, consistent with the finding of non-inferiority of TCZ mono compared with TCZ + MTX in patients with RA who achieve low disease activity with TCZ + MTX. Acknowledgement This study was funded by Genentech, Inc. Disclosure of Interests D. James Haddon Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Thierry Sornasse Employee of: Genentech, Inc., Michael J. Townsend Shareholder of: Stockholder of Genentech/Roche, Employee of: Genentech/Roche, Jinglan Pei Employee of: Genentech, Margaret Michalska Employee of: Genentech, Inc.

Background Risk factors for treatment failure in patients with giant cell arteritis (GCA) are poorly understood. Objectives To identify predictors of treatment failure in GCA patients receiving tocilizumab (TCZ) or placebo (PBO) in combination with prednisone in a randomized controlled trial.1 Methods Two hundred fifty GCA patients received weekly or every-other-week TCZ plus a 26-week prednisone taper (TCZ+pred) or PBO plus a 26- or 52-week prednisone taper (PBO+pred). Patients who achieved and maintained clinical remission (CR) from week 12 to week 52 while adhering to the protocol prednisone taper were classified as responders. CR, adjudicated by investigators, was defined as the absence of disease flare (GCA signs or symptoms, and/or ESR elevation attributable to GCA that required further treatment [eg, rescue prednisone]) regardless of CRP level. Treatment failure was defined as failure to achieve CR by week 12 or occurrence of flare between weeks 12 and 52. Both TCZ groups and both PBO groups were combined for this analysis. Potential predictors investigated included baseline demographics, disease- and treatment-related factors, and health-related quality of life (HRQOL) measures. Univariate and multivariate analyses were performed. Results Overall, 45% (113/250) of patients were responders: 27% (27/101) in the PBO+pred groups and 58% (86/149) in the TCZ+pred groups. In contrast, 44% (111/250) of patients experienced treatment failure: 66% (67/101) in the PBO+pred group and 30% (44/149) in the TCZ+pred group. The other 10% (26/250) of patients were nonresponders for reasons other than treatment failure: 7 in the PBO+pred group and 19 in the TCZ+pred group. In univariate analysis, female sex and lower baseline SF-36 Physical Component Summary (PCS), Mental Component Summary, and FACIT-Fatigue scores were associated with treatment failure among PBO+pred–treated patients, whereas higher patient global assessment of disease activity scores and lower SF-36 PCS, FACIT-Fatigue, and EQ-5D scores were associated with treatment failure among TCZ+pred–treated patients (Figure 1). Among TCZ+pred–treated patients, no treatment response difference according to sex was observed. Age, previous relapse, starting prednisone dose, and GCA clinical features (cranial or polymyalgia rheumatica symptoms) were not associated with treatment failure in either group based on univariate analysis. Multivariate logistic regression demonstrated that PBO+pred treatment, female sex, worse FACIT-Fatigue scores at baseline, and historical CRP >2.5 mg/dL all independently increased the risk for treatment failure (Figure 2). Conclusion Female GCA patients responded particularly poorly if treated with prednisone alone according to univariate analysis. Female sex, impaired HRQOL at baseline, history of elevated CRP, and treatment with prednisone alone are independent risk factors for treatment failure in GCA. These factors may be considered when determining which treatment would be best for a particular patient. References [1] Stone JH, et al. N Engl J Med. 2017;377:317-328. Disclosure of Interests Sebastian Unizony Grant/research support from: F. Hoffmann-La Roche, Genentech, Consultant for: Kiniksa, Sanofi, GSK, Min Bao Shareholder of: F. Hoffmann-La Roche Ltd., Employee of: Genentech, Jian Han Shareholder of: F. Hoffmann-La Roche Ltd., Employee of: Genentech, Yves Luder Shareholder of: F. Hoffmann-La Roche, Employee of: F. Hoffmann-La Roche, Paris Sidiropoulos Employee of: Genentech, Jinglan Pei Employee of: Genentech, John H. Stone Grant/research support from: F. Hoffmann-La Roche, Genentech, Xencor, Consultant for: Chugain, F. Hoffmann-La Roche, Genentech, Xencor

Background Previously, the GiACTA study demonstrated the superiority of subcutaneous (SC) tocilizumab (TCZ) plus prednisone vs prednisone alone in achieving sustained glucocorticoid (GC)-free remission in patients with giant cell arteritis (GCA).1 Objectives To evaluate the effectiveness and safety of SC and intravenous TCZ in real-world clinical practice. Methods We performed a retrospective analysis of GCA patients treated with TCZ at a single center (MGH) between 2010-2018. Annual relapse rate, time to disease relapse, number of relapses, prednisone use, and adverse events (AE) before and after TCZ initiation were assessed. Disease relapse was defined as the re-appearance of clinical manifestations of GCA (e.g., cranial symptoms) that required treatment modification. Results A total of 60 GCA patients were included in the analysis. Table 1 depicts the baseline characteristics and the treatments received by this cohort. The median (IQR) disease duration before TCZ use was 0.6 (0.2-1.6) years. Fifty-eight patients (96.7%) received concomitant prednisone (mean [SD] dose: 30 [18.3] mg daily) at the time of TCZ initiation. Patients received TCZ for a median (IQR) period of 0.5 (0.3-1.4) years. Before TCZ treatment, 43 patients (71.7%) had ≥1 relapse (median [IQR] time to relapse 0.5 [0.3-0.7] years). After TCZ initiation, 18 patients (30.0%) had ≥1 relapse (estimated median [IQR] time to relapse 2.1 [0.6-2.3] years). The annual rate of relapse was lower on TCZ than while off TCZ (RR=0.40 [95% CI, 0.25-0.63]; P=0.0001) (Table 2). Twenty-seven patients (46.6%) successfully tapered off prednisone during TCZ treatment. The incidence of AEs and serious AEs (SAE) was similar before and after TCZ initiation (Table 2). During TCZ treatment, however, 38 of 81 AEs were considered related or possibly related to prednisone. An AE led to TCZ discontinuation in 5 patients. No deaths occurred during the study period. Conclusion In this retrospective analysis, TCZ improved clinical outcomes in patients with GCA as indicated by a reduced incidence of relapses and by the ability to discontinue prednisone. The occurrence of AEs and SAEs (many due to GC) did not differ substantially while patients were on or off TCZ. These real-world findings support the previously reported efficacy and safety profile of TCZ in patients with GCA. Reference [1] Stone JH, et al. N Engl J Med. 2017;377(4):317-328. Disclosure of Interests Sebastian Unizony Grant/research support from: F. Hoffmann-La Roche, Genentech, Consultant for: Kiniksa, Sanofi, GSK, Jinglan Pei Employee of: Genentech, Paris Sidiropoulos Employee of: Genentech, Jennie H. Best Shareholder of: Genentech, Employee of: Genentech, Christine Birchwood Employee of: Genentech, John H. Stone Grant/research support from: F. Hoffmann-La Roche, Genentech, Xencor, Consultant for: Chugain, F. Hoffmann-La Roche, Genentech, Xencor

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 β-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 β-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 β-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 β-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

ObjectiveSubcutaneous (SC) and intravenous formulations of tocilizumab (TCZ) are available for the treatment of patients with rheumatoid arthritis (RA), based on the efficacy and safety observed in clinical trials. Anti-TCZ antibody development and its impact on safety and efficacy were evaluated in adult patients with RA treated with intravenous TCZ (TCZ-IV) or TCZ-SC as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).MethodsData from 5 TCZ-SC and 8 TCZ-IV phase III clinical trials and 1 TCZ-IV clinical pharmacology safety study (>50 000 samples) were pooled to assess the immunogenicity profile of TCZ-SC and TCZ-IV (8974 total patients). The analysis included antidrug antibody (ADA) measurement following TCZ-SC or TCZ-IV treatment as monotherapy or in combination with csDMARDs, after dosing interruptions or in TCZ-washout samples, and the correlation of ADAs with clinical response, adverse events or pharmacokinetics (PK).ResultsThe proportion of patients who developed ADAs following TCZ-SC or TCZ-IV treatment was 1.5% and 1.2%, respectively. ADA development was also comparable between patients who received TCZ monotherapy and those who received concomitant csDMARDs (0.7–2.0%). ADA development did not correlate with PK or safety events, including anaphylaxis, hypersensitivity or injection-site reactions, and no patients who developed ADAs had loss of efficacy.ConclusionsThe immunogenicity risk of TCZ-SC and TCZ-IV treatment was low, either as monotherapy or in combination with csDMARDs. Anti-TCZ antibodies developed among the small proportion of patients had no evident impact on PK, efficacy or safety.

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.

Supplemental material, MSJ808189_CONSORT_checklist for Ocrelizumab reduces progression of upper extremity impairment in patients with primary progressive multiple sclerosis: Findings from the phase III randomized ORATORIO trial by Edward J Fox, Clyde Markowitz, Angela Applebee, Xavier Montalban, Jerry S Wolinsky, Shibeshih Belachew, Damian Fiore, Jinglan Pei, Bruno Musch and Gavin Giovannoni in Multiple Sclerosis Journal

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.

Vorapaxar, a novel antiplatelet agent in advanced clinical development for the prevention and treatment of atherothrombotic disease, is a potent, orally bioavailable thrombin receptor antagonist selective for the protease-activated receptor 1 (PAR-1).Since race/ethnicity may affect the safety, efficacy and dosage of drugs, this study was conducted to evaluate potential differences in the pharmacodynamics, pharmacokinetics and safety of vorapaxar after single (5, 10, 20, or 40 mg) or multiple (0.5, 1, or 2.5 mg once daily) doses in healthy Japanese and matched (gender, age, height, and weight) Caucasian volunteers.Vorapaxar was well tolerated in both Japanese and Caucasian subjects. Pharmacodynamic and pharmacokinetic profiles of vorapaxar in the two racial/ethnic groups were similar. In both racial groups, complete inhibition of platelet aggregation was achieved most rapidly with vorapaxar 40 mg and was consistently achieved and maintained with a 2.5 mg daily maintenance dose.There were no substantial differences in the safety, pharmacokinetics or pharmacodynamics of vorapaxar between Japanese and Caucasian subjects.

Summary Background An antithrombotic drug is needed that safely reduces cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We therefore assessed the tolerability and safety of SCH 530348—an oral platelet protease-activated receptor-1 antagonist. Methods We randomly assigned patients aged 45 years or older and undergoing non-urgent PCI or coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio in a multicentre international study. Those in the SCH 530348 group who subsequently underwent PCI (primary PCI cohort) continued taking an oral maintenance dose (0·5 mg, 1·0 mg, or 2·5 mg per day), and patients in the placebo group continued placebo for 60 days. The primary endpoint was the incidence of clinically significant major or minor bleeding according to the thrombolysis in myocardial infarction (TIMI) scale. Both investigators and patients were unaware of treatment allocation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00132912. Findings 257 patients were assigned to placebo and 773 to SCH 530348. The primary endpoint occurred in 2 (2%) of 129, 3 (3%) of 120, and 7 (4%) of 173 patients, respectively, in the SCH 530348 10 mg, 20 mg, and 40 mg groups compared with 5 (3%) of 151 patients in the placebo group (p=0·5786). TIMI major plus minor bleeding occurred in 3 (2%) of 136, 5 (4%) of 139, and 4 (3%) of 138 patients given SCH 530348 0·5 mg, 1·0 mg, and 2·5 mg once per day, respectively (p=0·7561). Interpretation Oral SCH 530348 was generally well tolerated and did not cause increased TIMI bleeding, even when administered concomitantly with aspirin and clopidogrel. Further testing in phase III trials to accurately define the safety and efficacy of SCH 530348 is warranted. Funding Schering-Plough Research Institute.

Objective. The American College of Rheumatology/European League Against Rheumatism established definitions of remission for rheumatoid arthritis (RA) based on composite scores including tender and swollen joint counts (TJC/SJC), Patient Global visual analog scale (VAS) score, laboratory tests, and, in Simplified Disease Activity Index (SDAI), Physician Global score. Time constraints on a physician's schedule demand an easy yet accurate tool to measure disease activity. We assessed the predictability of Routine Assessment of Patient Index Data 3 (RAPID3) with/without a single swollen joint versus SDAI and/or Boolean remission criteria for functional and radiographic outcomes. Methods. Data were from the tociLIzumab Safety and THE Prevention of Structural Joint Damage (LITHE) phase 3 trial in RA patients. The ability, at year 1, of RAPID3 ≤3 + 1 SJC, RAPID3 ≤3 (remission) without SJC, SDAI ≤3.3 (remission) and/or Boolean remission (SJC,TJC, Patient Global VAS, and C-reactive protein [mg/dL] all ≤1) to predict year 2 Health Assessment Questionnaire–Disability Index (HAQ-DI) score ≤0.5 (normal), no worsening of HAQ-DI score from year 1, and no worsening of Genant-modified Total Sharp Score from year 1 was assessed. Results. Among 690 patients, mean (SD) baseline Disease Activity Score at 28 joints (DAS28) was 6.5 (0.96), RAPID3 score was 14.2 (5.51), and SDAI score was 41.7 (13.01). Achieving year 1 measures was associated with good functional and radiographic outcomes at year 2. Sensitivity/specificity/positive predictive values/negative predictive values were 49.1%/83.2%/37.4%/88.9% (RAPID3 remission), 26.4%/91.7%/36.8%/87.1% (RAPID3 + 1SJC), 26.7%/90.9%/37.3%/85.9% (SDAI remission), and 17.0%/96.6%/47.4%/86.4% (Boolean remission). Conclusion. The predictability of RAPID3 (with or without joint count) was similar to that of SDAI and Boolean criteria. This article is protected by copyright. All rights reserved.

Background Two global Phase III studies evaluated the safety and efficacy of subcutaneous tocilizumab (TCZ-SC). SUMMACTA was a 97-week study that compared TCZ-SC 162 mg every week (qw) with intravenous TCZ (TCZ-IV) 8 mg/kg every 4 weeks. At week 24, patients (pts) were re-randomized to remain on the initially assigned formulation or switch to the other formulation. BREVACTA was a 96-week study that compared TCZ-SC 162 mg every 2 weeks (q2w) with placebo. From week 12 onward, pts could escape to TCZ-SC qw if they had Objectives To assess long-term safety and efficacy of TCZ-SC in US pts who completed the SUMMACTA or BREVACTA core studies. Methods In this open-label, single-arm, US-based, Phase IIIb study, pts who completed SUMMACTA and BREVACTA could enroll and continue to receive their dosage of TCZ-SC q2w or qw, or switch from TCZ-IV to TCZ-SC qw. Nonbiologic disease-modifying antirheumatic drugs in combination with TCZ-SC were permitted. The primary safety endpoint was the proportion of pts with serious adverse events (SAEs). Secondary endpoints included the proportions of pts with adverse events of special interest and pts who discontinued, incidence of laboratory abnormalities and efficacy assessments. Results Of 217 pts treated, 76.5% were female and mean age was 58.4 years. A total of 23 pts (10.6%) had ≥1 SAEs, for a rate of 14.7/100 pt-years (Table). The most common SAEs were infections (n=7, 3.2%). Eight pts had ≥1 serious or opportunistic infections or infections requiring IV anti-infectives. Thirty-four pts withdrew from TCZ-SC treatment, 13 (6.0%) due to AEs, 21 (9.7%) due to nonsafety reasons. Aminotransferase elevations were reported in 27.2% of pts but were not associated with liver toxicity. Neutropenia (5.1%) was transient. Injection site reactions occurred in 6 patients, were nonserious and resolved without sequelae. No anaphylaxis or deaths were reported. Mean Clinical Disease Activity Index and 28-joint Disease Activity Scores (DAS28) decreased from baseline and remained stable thereafter. Conclusions The safety of TCZ-SC during the long-term extension period of the SUMMACTA and BREVACTA studies was consistent with the safety profile established during the core studies, with no new safety signals identified. Mean efficacy improvements observed from baseline were stable over time. These results demonstrate the durability of the safety and efficacy responses with long-term exposure to TCZ-SC. Disclosure of Interest A. Kivitz Grant/research support from: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Genentech, Janssen, Pfizer, UCB, Consultant for: BMS, Genentech, UCB, Speakers bureau: BMS, E. Olech Grant/research support from: Genentech, Consultant for: Genentech, M. Borofsky: None declared, J. Devenport Employee of: Genentech, J. Pei Employee of: Genentech, T. Wallace Employee of: Genentech, M. Michalska Employee of: Genentech

Introduction To assess the long-term safety and efficacy of subcutaneous tocilizumab (TCZ-SC) in US patients with rheumatoid arthritis (RA) who rolled over from the two global phase 3 studies, SUMMACTA (NCT01194414) and BREVACTA (NCT1232569), into this open-label, single-arm, phase 3b study. Methods Patients continued to receive TCZ-SC 162 mg weekly or every other week or switched from intravenous TCZ to TCZ-SC 162 mg qw for up to 84 weeks. The primary endpoint was the proportion of patients with serious adverse events (SAEs). Secondary endpoints included clinical efficacy, laboratory abnormalities, and immunogenicity. Results Of the 217 patients treated, 76.5% were female, and the mean age was 58.4 years. A total of 23 patients (10.6%) had ≥1 SAE. The most common SAEs were infections (3.7%). Alanine aminotransferase elevations (38.2%) were not associated with hepatic injury. Grade 3/4 neutropenia (3%) was transient and not associated with serious infections. Immunogenicity was low (