Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial.

OBJECTIVES: To evaluate the efficacy and safety of intravenous ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, active rheumatoid arthritis (RA) patients despite methotrexate treatment. METHODS: In this double-blind, placebo-controlled, phase III study, active RA patients on stable methotrexate were randomly assigned to one course of two infusions of ofatumumab 700 mg (n=130) or placebo (n=130), 2 weeks apart. The primary endpoint was the ACR20 response at week 24. Secondary endpoints included ACR50/70, EULAR response, disease activity score based on 28 joints using C-reactive protein, adverse events (AE) and immunogenicity. RESULTS: At week 24, a greater proportion of patients on ofatumumab compared with placebo achieved an ACR20 response (50% vs 27%, p<0.001) and a good or moderate EULAR response (67% vs 41%, p<0.001). All other key secondary efficacy endpoints were significantly improved on ofatumumab. Efficacy observed by 8 weeks was sustained throughout the study. The most common AE for ofatumumab versus placebo were rash (21% vs <1%) and urticaria (12% vs <1%), mostly occurring on the first infusion day. Overall, first-dose infusion reactions were 68% for ofatumumab and 6% for placebo, mostly mild to moderate; second-dose infusion reactions markedly declined (<1% and 0%). Serious AE were reported in 5% of ofatumumab versus 3% of placebo patients. Infection rates were 32% and 26% (serious infections <1% and 2%), respectively. One death (interstitial lung disease), unrelated to study drug, was reported on ofatumumab. No antidrug antibodies were detected in ofatumumab patients. CONCLUSIONS: Ofatumumab significantly improved all clinical outcomes in biological-naive, active RA patients with no detectable immunogenicity at week 24. No unexpected safety findings were identified. Trial Registry clinical trials.gov registration number NCT00611455.

Ultrastructural descriptions of heterotypic aggregation between eosinophils and tumor cells in human gastric carcinomas.

A histological variant of gastric adenocarcinoma, characterized by an intense tumor-associated tissue eosinophilia (TATE), has been occasionally reported in the literature. The purpose of this ultrastructural study was to determine the interactions between frequently occurring eosinophils and tumor cells in gastric carcinoma characterized by TATE. Fresh tumor tissue of 92 gastric carcinomas was processed for both light and electron microscopic examination. Intense TATE was found in 7 out of 92 (7.6%) gastric carcinomas (6 of intestinal-type and 1 of diffuse-type). Electron microscopy, selectively performed in 7 cases with intense TATE, revealed eosinophils, singly or in groups, in contact with damaged or necrotic tumor cells. Activated eosinophils showing piecemeal degranulation were also found in intimate contact with viable tumor cells, characterized by plasma membrane caveolar invaginations. The authors regard this close morphological relationship as in vivo evidence for possible cross-talk between eosinophil and viable tumor cell, a conclusion that has already been drawn from experimental studies, but until now inadequately supported by ultrastructural observations in a human tumor.

A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis.

BACKGROUND: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA). METHODS: Patients with moderate to severe RA who had received ≥12 weeks' stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85. RESULTS: A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints-C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms. CONCLUSIONS: These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02858492 . Registered 8 August 2016.

Developing Smartphone-Based Objective Assessments of Physical Function in Rheumatoid Arthritis Patients: The PARADE Study.

BACKGROUND: Digital biomarkers that measure physical activity and mobility are of great interest in the assessment of chronic diseases such as rheumatoid arthritis, as it provides insights on patients' quality of life that can be reliably compared across a whole population. OBJECTIVE: To investigate the feasibility of analyzing iPhone sensor data collected remotely by means of a mobile software application in order to derive meaningful information on functional ability in rheumatoid arthritis patients. METHODS: Two objective, active tasks were made available to the study participants: a wrist joint motion test and a walk test, both performed remotely and without any medical supervision. During these tasks, gyroscope and accelerometer time-series data were captured. Processing schemes were developed using machine learning techniques such as logistic regression as well as explicitly programmed algorithms to assess data quality in both tasks. Motion-specific features including wrist joint range of motion (ROM) in flexion-extension (for the wrist motion test) and gait parameters (for the walk test) were extracted from high quality data and compared with subjective pain and mobility parameters, separately captured via the application. RESULTS: Out of 646 wrist joint motion samples collected, 289 (45%) were high quality. Data collected for the walk test included 2,583 samples (through 867 executions of the test) from which 651 (25%) were high quality. Further analysis of high-quality data highlighted links between reduced mobility and increased symptom severity. ANOVA testing showed statistically significant differences in wrist joint ROM between groups with light-moderate (220 participants) versus severe (36 participants) wrist pain (p < 0.001) as well as in average step times between groups with slight versus moderate problems walking about (p < 0.03). CONCLUSION: These findings demonstrate the potential to capture and quantify meaningful objective clinical information remotely using iPhone sensors and represent an early step towards the development of patient-centric digital endpoints for clinical trials in rheumatoid arthritis.

Ultrastructural observations on inflammatory angiogenesis in gastric carcinomas with massive neutrophil infiltration.

Neutrophils are traditionally thought of as terminal effectors of inflammatory reaction, but experimental studies suggest that they play a direct role in the inflammatory angiogenesis of tumors. Thus, further evidence in humans is required regarding the mechanisms by which neutrophils induce tumor angiogenesis. In this study, 4 cases of human gastric carcinomas with massive neutrophil infiltration were studied by light and electron microscopy, focusing on the inflammatory angiogenesis in the tumor stroma. At light microscopy, the tumors were advanced gastric carcinomas in which various degrees of tubular differentiation were present. Under an electron microscope, pericytes exhibited two major differentiated states with distinct ultrastructural features: a contractile phenotype and a synthetic phenotype. The contractile phenotype was characterized by abundant microfilaments. Synthetic pericytes contained abundant rough endoplasmic reticulum, lipid bodies, and numerous membrane-bound vesicles. These ultrastructural findings extend concept of contractile/synthetic phenotype modulation, originally described in smooth muscle cells, to tumor microvascular pericytes. Tumor microvasculature was also characterized by abortive or slit-like lumina, endothelial cell mitoses, and replicating basement membranes. These qualitative and observational transmission electron microscopy findings provide additional morphological evidence of active inflammatory angiogenesis in gastric carcinomas with massive neutrophil infiltration.

Using a ResearchKit Smartphone App to Collect Rheumatoid Arthritis Symptoms From Real-World Participants: Feasibility Study.

BACKGROUND: Using smartphones to enroll, obtain consent, and gather self-reported data from patients has the potential to enhance our understanding of disease burden and quantify physiological impact in the real world. It may also be possible to harness integral smartphone sensors to facilitate remote collection of clinically relevant data. OBJECTIVE: We conducted the Patient Rheumatoid Arthritis Data From the Real World (PARADE) observational study using a customized ResearchKit app with a bring-your-own-device approach. Our objective was to assess the feasibility of using an entirely digital approach (social media and smartphone app) to conduct a real-world observational study of patients with rheumatoid arthritis. METHODS: We conducted this observational study using a customized ResearchKit app with a bring-your-own-device approach. To recruit patients, the PARADE app, designed to guide patients through a series of tasks, was publicized via social media platforms and made available for patients in the United States to download from the Apple App Store. We collected patient-reported data, such as medical history, rheumatoid arthritis-related medications (past and present), and a range of patient-reported outcome measures. We included in the assessment a joint-pain map and a novel objective assessment of wrist range of movement, measured by the smartphone-embedded gyroscope and accelerometer. RESULTS: Within 1 month of recruitment via social media campaigns, 399 participants self-enrolled, self-consented, and provided complete demographic data. Joint pain was the most frequently reported rheumatoid arthritis symptom to bother study participants (344/393, 87.5%). Severe patient-reported wrist pain appeared to be inversely linked with the range of wrist movement measured objectively by the app. At study entry, 292 of 399 participants (73.2%) indicated a preference for participating in a mobile app-based study. The number of participants in the study declined to 45 of 399 (11.3%) at week 12. CONCLUSIONS: Despite the declining number of participants over time, the combination of social media and smartphone app with sensor integration was a feasible and cost-effective approach for the collection of patient-reported data in rheumatoid arthritis. Integral sensors within smartphones can be harnessed to provide novel end points, and the novel wrist range of movement test warrants further clinical validation.

Safety of Repeated Open-Label Treatment Courses of Intravenous Ofatumumab, a Human Anti-CD20 Monoclonal Antibody, in Rheumatoid Arthritis: Results from Three Clinical Trials.

OBJECTIVES: To investigate the safety of ofatumumab retreatment in rheumatoid arthritis. METHODS: Patients with active rheumatoid arthritis participating in two phase III trials (OFA110635 and OFA110634) and a phase II extension trial (OFA111752) received individualised open-label ofatumumab retreatment (700 mg X 2 intravenous infusions two weeks apart) ≥24 weeks following the first course and ≥16 weeks following further courses. Retreatment required evidence of clinical response followed by disease relapse. These studies were prematurely terminated by the sponsor to refocus development on subcutaneous delivery. Due to differences in study designs and populations, data are summarised separately for each study. RESULTS: 483 patients (243, 148 and 92 in OFA110635, OFA110634 and OFA111752 respectively) received up to 7 treatment courses of intravenous ofatumumab; cumulative duration of exposure was 463, 182 and 175 patient-years, respectively. Mean time between courses was 17-47 weeks. Ofatumumab induced a profound depletion of peripheral B-lymphocytes. Retreated patients derived benefit based on improvement in DAS28. Adverse events were reported for 93% (226/243), 91% (134/148) and 76% (70/92), serious adverse events for 18% (44/243), 20% (30/148) and 12% (11/92) and serious infections for 3% (8/243), 5% (7/148) and 1% (1/92) of patients in OFA110635, OFA110634 and OFA111752, respectively. The most common adverse events were infusion-related reactions during the first infusion of the first course (48-79%); serious infusion-related reactions were rare (<1% [1/243], 5% [8/148], and 1% [1/92] of patients). Two deaths occurred (fulminant hepatitis B virus infection and interstitial lung disease). CONCLUSIONS: Ofatumumab was generally well tolerated with no evidence of increased safety risks with multiple retreatments. Serious infections were uncommon and did not increase over time. TRIAL REGISTRATION: ClinicalTrials.gov 110635 ClinicalTrials.gov 110634 ClinicalTrials.gov 111752.

Epidemiology and Treatment of New-Onset and Established Rheumatoid Arthritis in an Insured US Population.

OBJECTIVE: To investigate the epidemiology and treatment of rheumatoid arthritis (RA) in a population broadly representative of employed adults in the US, using a retrospective cohort design. METHODS: Incident and prevalent RA cohorts were defined from a sample of 4.66 million adults with complete followup data from the period of January 2005 through September 2008 in the Pharmetrics medical claims database. Demographics, comorbidity, and medical therapies were summarized using descriptive statistics. RESULTS: Median duration in the database was 5.7 years. Age- and sex-adjusted incidence in 2006 was 0.71 per 1,000 persons at risk (n = 3,992) and prevalence in 2005 was 0.63% (n = 30,530). Within 12 months after diagnosis, 65%, 64%, and 20% of the incident cohort had been prescribed corticosteroids, nonbiologic disease-modifying antirheumatic drugs (DMARDs), and tumor necrosis factor (TNF) inhibitors, respectively. Median time to first anti-TNF prescription was 6 months; 31% switched to a second drug and 15% to a third. An aggressive subcohort (11% of incident patients) received more DMARDs (83%) and TNF inhibitors (43%), and was more likely to switch. Twenty-eight percent of incident patients received only symptomatic therapy over a minimum of 1.75 years of followup; these patients were older with more comorbidities and contraindications to methotrexate. CONCLUSION: In this insured population-based cohort, only two-thirds of newly diagnosed RA patients were prescribed a DMARD in year 1 and 28% received no antirheumatic therapy. Although limited by lack of clinical information and by left-censoring, administrative databases capture clinical practice and suggest that gaps exist in treatment options available to a significant number of patients.

Apoptotic-like tumor cells and apoptotic neutrophils in mitochondrion-rich gastric adenocarcinomas: a comparative study with light and electron microscopy between these two forms of cell death.

Mitochondrion-rich adenocarcinomas represent a rare variant of gastric adenocarcinomas composed predominantly of columnar adenocarcinoma cells with eosinophilic cytoplasm, a strong supranuclear immunoreactivity for antimitochondrial antibody, and a marked neutrophil infiltration associated to tumor cell death. The purpose of this work is to investigate, using correlated light and electron microscopy, mitochondrion-rich gastric adenocarcinomas focusing on the nature of the death in neoplastic cells and in infiltrating neutrophils. Adenocarcinoma cells, single or in small clusters, showed convoluted nuclei, irregularly condensed chromatin, loss of microvilli, and nuclear envelope dilatation. No nuclear fragmentation was observed in these dying cells and the plasma membrane did not show signs of disruption. These ultrastructural findings represent intermediate aspects between apoptosis and necrosis and are compatible with apoptosis-like programmed cell death. By contrast, some infiltrating neutrophils showed ultrastructural signs of classic apoptosis such as chromatin condensation into compact geometric (globular, crescentshaped) figures, tightly packed cytoplasmic granules and intact cell membrane. Our study provides ultrastructural evidence of apoptosislike tumour cell death in mitochondrion-rich gastric carcinomas and confirms that stereotyped outcome either as apoptosis or necrosis of tumor cells cannot always be expected in human neoplasms.

Histologic coagulative tumour necrosis as a prognostic indicator of aggressiveness in renal, lung, thyroid and colorectal carcinomas: A brief review.

Tumour growth involves two essential deviations from the normal state including the induction of proliferative stimuli, and simultaneous suppression of potentially compensatory cell death. It has been suggested that the development of invasive cancer involves a progressive switch from predominantly apoptotic to necrotic tumour cell death. The presence of tumour necrosis in pathologic specimens may not only reflect tumour biology, but also provide additional beneficial prognostic information. This review emphasises the role of tumour necrosis as an additional prognostic factor for patients with certain types of epithelial neoplasms.

High-efficiency gene transfer into nontransformed cells: utility for studying gene regulation and analysis of potential therapeutic targets.

The elucidation of the signalling pathways involved in inflammatory diseases, such as rheumatoid arthritis, could provide long sought after targets for therapeutic intervention. Gene regulation is complex and varies depending on the cell type, as well as the signal eliciting gene activation. However, cells from certain lineages, such as macrophages, are specialised to degrade exogenous material and consequently do not easily transfect. Methods for high-efficiency gene transfer into primary cells of various lineages and disease states are desirable, as they remove the uncertainties associated with using transformed cell lines. Significant research has been undertaken into the development of nonviral and viral vectors for basic research, and as vehicles for gene therapy. We briefly review the current methods of gene delivery and the difficulties associated with each system. Adenoviruses have been used extensively to examine the role of various cytokines and signal transduction molecules in the pathogenesis of rheumatoid arthritis. This review will focus on the involvement of different signalling molecules in the production of tumour necrosis factor alpha by macrophages and in rheumatoid synovium. While the NF-kappaB pathway has proven to be a major mediator of tumour necrosis factor alpha production, it is not exclusive and work evaluating the involvement of other pathways is ongoing.