Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study.

BACKGROUND: Refractory coeliac disease type 2 is a rare subtype of coeliac disease with high mortality rates; interleukin 15 (IL-15) is strongly implicated in its pathophysiology. This trial aimed to investigate the effects of AMG 714, an anti-IL-15 monoclonal antibody, on the activity and symptoms of refractory coeliac disease type 2. METHODS: This was a randomised, double-blind, placebo-controlled, phase 2a study of adults with a confirmed diagnosis of refractory coeliac disease type 2. Patients were randomly assigned at a 2:1 ratio to receive seven intravenous doses over 10 weeks of AMG 714 (8 mg/kg) or matching placebo. Biopsy samples were obtained at baseline and week 12 for cellular analysis and histology. The change in the proportion of aberrant intraepithelial lymphocytes from baseline to week 12 with respect to all intraepithelial lymphocytes was the primary endpoint and was quantified using flow cytometry. Secondary endpoints were the change in aberrant intraepithelial lymphocytes with respect to intestinal epithelial cells; intestinal histological scores (villous height-to-crypt depth ratio; VHCD); intraepithelial lymphocyte counts; Marsh score; and patient-reported symptom measures, including the Bristol stool form scale (BSFS) and gastrointestinal symptom rating scale (GSRS). Main analyses were done in the per-protocol population of patients who received their assigned treatment, provided evaluable biopsy samples, and did not have major protocol deviations; only patients with non-atypical disease were included in the analyses of aberrant intraepithelial lymphocytes, including the primary analysis. Safety was assessed in all patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02633020) and EudraCT (2015-004063-36). FINDINGS: From April 13, 2016, to Jan 19, 2017, 28 patients were enrolled and randomly assigned to AMG 714 (n=19) and placebo (n=9). Six patients were not included in the primary analysis because of protocol deviation (one in the AMG 714 group), insufficient biopsy samples (one in the AMG 714 group), and atypical intraepithelial lymphocytes (three in the AMG 714 group and one in the placebo group). At 12 weeks, the least square mean difference between AMG 714 and placebo in the relative change from baseline in aberrant intraepithelial lymphocyte percentage was -4·85% (90% CI -30·26 to 20·56; p=0·75). The difference between the AMG 714 and placebo groups in aberrant intraepithelial lymphocytes with respect to epithelial cells at 12 weeks was -38·22% (90% CI -95·73 to 19·29; nominal p=0·18); the difference in change in Marsh score from baseline was 0·09% (95% CI -1·60-1·90; nominal p=0·92); the difference in VHCD ratio was 10·67% (95% CI -38·97 to 60·31; nominal p=0·66); and the difference in change in total intraepithelial lymphocyte count was -12·73% (95% CI -77·57-52·12); nominal p=0·69). Regarding symptoms, the proportion of patients with diarrhoea per the BSFS score decreased from ten (53%) of 19 at baseline to seven (37%) of 19 at week 12 in the AMG 714 group and increased from two (22%) of nine at baseline to four (44%) of nine at week 12 in the placebo group (nominal p=0·0008); and the difference between the groups in change in GSRS score was -0·14 (SE 0·19; nominal p=0·48). Eight (89%) patients in the placebo group and 17 (89%) in the AMG 714 group had treatment-emergent adverse events, including one (11%) patient in the placebo group and five (26%) in the AMG 714 group who had serious adverse events. The most common adverse event in the AMG 714 group was nasopharyngitis (eight [42%] patients vs one [11%] in the placebo group). INTERPRETATION: In patients with refractory coeliac disease type 2 who were treated with AMG 714 or placebo for 10 weeks, there was no difference between the groups in terms of the primary endpoint of aberrant intraepithelial lymphocyte reduction from baseline. Effects on symptoms and other endpoints suggest that further research of AMG 714 may be warranted in patients with refractory coeliac disease type 2. FUNDING: Celimmune and Amgen.

Brief Report: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multiple-Dose Study to Evaluate AMG 557 in Patients With Systemic Lupus Erythematosus and Active Lupus Arthritis.

OBJECTIVE: To evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus (SLE) with arthritis. METHODS: In this phase Ib, randomized, double-blind, placebo-controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), ≥1-letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). RESULTS: The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a ≥4-point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (-36.3% versus -24.7%) and the SLEDAI score (-47.8% versus -10.7%) and in tender (-22.8% versus -13.5%) and swollen (-62.1% versus -7.8%) joint counts on day 169. CONCLUSION: AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.

Corrigendum: The RA-MAP Consortium: a working model for academia-industry collaboration.

This corrects the article DOI: 10.1038/nrrheum.2017.200.

The RA-MAP Consortium: a working model for academia-industry collaboration.

Collaboration can be challenging; nevertheless, the emerging successes of large, multi-partner, multi-national cooperatives and research networks in the biomedical sector have sustained the appetite of academics and industry partners for developing and fostering new research consortia. This model has percolated down to national funding agencies across the globe, leading to funding for projects that aim to realise the true potential of genomic medicine in the 21st century and to reap the rewards of 'big data'. In this Perspectives article, the experiences of the RA-MAP consortium, a group of more than 140 individuals affiliated with 21 academic and industry organizations that are focused on making genomic medicine in rheumatoid arthritis a reality are described. The challenges of multi-partner collaboration in the UK are highlighted and wide-ranging solutions are offered that might benefit large research consortia around the world.

Safety, tolerability, pharmacokinetics, and efficacy of AMG 403, a human anti-nerve growth factor monoclonal antibody, in two phase I studies with healthy volunteers and knee osteoarthritis subjects.

INTRODUCTION: Nerve growth factor plays a key role in the pathology of osteoarthritis (OA) related chronic pain. The aim of these studies was to evaluate the safety, tolerability, pharmacokinetics, and clinical response of AMG 403, a human anti-nerve growth factor monoclonal antibody, in healthy volunteers and subjects with knee OA. METHODS: Two phase I, randomized, placebo-controlled, double-blind studies were conducted. The single-ascending dose study randomized healthy volunteers (n = 48) 3:1 to receive AMG 403 (1, 3, 10, or 30 mg intravenously; or 10 or 30 mg subcutaneously; n = 8 per group) or placebo. The multiple-ascending dose study randomized knee OA subjects (n = 18) 3:1 to receive AMG 403 (3, 10, or 20 mg subcutaneously once monthly for four doses) or placebo. Safety, tolerability, and pharmacokinetics (PK) were assessed for both studies. Patient's and physician's disease assessments and total WOMAC score were determined in knee OA subjects. RESULTS: AMG 403 appeared to be well-tolerated after single and multiple doses, except for subject-reported hyperesthesia, pain, and paresthesia (mild to moderate severity). These treatment-emergent neurosensory events showed evidence of reversibility and a possible dose-dependence. Three serious adverse events were reported in AMG 403 treated subjects, but were not considered treatment related. AMG 403 PK was linear with an estimated half-life of 19.6 to 25.8 days. After multiple doses, AMG 403 PK showed modest accumulation (≤2.4-fold increase) in systemic exposure. Knee OA diagnosis, body weight, and anti-drug antibody development did not appear to affect AMG 403 PK. Patient's and physician's disease assessments and total WOMAC score showed improvement in AMG 403 treated knee OA subjects compared with placebo. CONCLUSIONS: AMG 403 was generally safe and well-tolerated in both healthy volunteers and knee OA patients, and exhibited linear pharmacokinetics. Preliminary clinical efficacy was observed in knee OA subjects. TRIAL REGISTRATION: ClinicalTrials.gov NCT02348879 . Registered 23 December 2014. Clintrials.gov NCT02318407 . Registered 2 December 2014.

Treatment of systemic lupus erythematosus patients with the BAFF antagonist "peptibody" blisibimod (AMG 623/A-623): results from randomized, double-blind phase 1a and phase 1b trials.

INTRODUCTION: Blisibimod is a potent B cell-activating factor (BAFF) antagonist that binds to both cell membrane-expressed and soluble BAFF. The goal of these first-in-human studies was to characterize the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of blisibimod in subjects with systemic lupus erythematosus (SLE). METHODS: SLE subjects with mild disease that was stable/inactive at baseline received either a single dose of blisibimod (0.1, 0.3, 1, or 3 mg/kg subcutaneous [SC] or 1, 3, or 6 mg/kg intravenous [IV]) or placebo (phase 1a; N = 54), or four weekly doses of blisibimod (0.3, 1, or 3 mg/kg SC or 6 mg/kg IV) or placebo (phase 1b; N = 63). Safety and tolerability measures were collected, and B cell subset measurements and pharmacokinetic analyses were performed. RESULTS: All subjects (93 % female; mean age 43.7 years) carried the diagnosis of SLE for ≥ 1 year. Single- and multiple-dose treatment with blisibimod produced a decrease in the number of naïve B cells (24-76 %) and a transient relative increase in the memory B cell compartment, with the greatest effect on IgD(-)CD27+; there were no notable changes in T cells or natural killer cells. With time, memory B cells reverted to baseline, leading to a calculated 30 % reduction in total B cells by approximately 160 days after the first dose. In both the single- and multiple-dosing SC cohorts, the pharmacokinetic profile indicated slow absorption, dose-proportional exposure from 0.3 through 3.0 mg/kg SC and 1 through 6 mg/kg IV, linear pharmacokinetics across the dose range of 1.0-6.0 mg/kg, and accumulation ratios ranging from 2.21 to 2.76. The relative increase in memory B cells was not associated with safety signals, and the incidence of adverse events, anti-blisibimod antibodies, and clinical laboratory abnormalities were comparable between blisibimod- and placebo-treated subjects. CONCLUSIONS: Blisibimod changed the constituency of the B cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0-6.0 mg/kg. The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases. TRIAL REGISTRATION: Clinicaltrials.gov NCT02443506 . Registered 11 May 2015. NCT02411136 Registered 7 April 2015.

Modeling the pharmacokinetic-pharmacodynamic relationship of the monoclonal anti-macaque-IL-15 antibody Hu714MuXHu in cynomolgus monkeys.

Hu714MuXHu is a recombinant chimeric murine-human monoclonal antibody directed against interleukin-15 (IL-15), a proinflammatory cytokine associated with memory CD8+ and natural killer (NK) T-cell activation and implicated in the pathogenesis of inflammatory diseases. A pharmacokinetic-pharmacodynamic (PK/PD) model was developed to describe the NK cell count reduction in cynomolgus monkeys after treatment with Hu714MuXHu. Cynomolgus monkeys were dosed with Hu714MuXHu in three studies: as a single dose at 0.1 or 1 mg·kg(-1) i.v.; weekly for 5 weeks at 0, 30, 60, or 150 mg·kg(-1) i.v. or 150 mg·kg(-1) s.c.; weekly for 13 weeks at 0, 5, 30, or 150 mg·kg(-1) s.c. Serum Hu714MuXHu concentration-time data were analyzed using noncompartmental analysis and the PK/NK cell count relationship was assessed via simultaneous PK/PD modeling. Hu714MuXHu PK was approximately dose-proportional between 0.1-150 mg·kg(-1) for i.v. and 5-150 mg·kg(-1) for s.c. administration with an elimination half-life of 12.7-18 days. Hu714MuXHu administration resulted in rapid and marked reductions in NK cell counts after the first dose which recovered fully after the serum Hu714MuXHu concentrations approached 0.1 µg·mL(-1) (assay limit of quantification). PK/PD modeled Hu714MuXHu effects on NK cells had an EC 50 of 0.09 µg·mL(-1). In summary, weekly i.v. or s.c. doses with Hu714MuXHu for up to 3 months in cynomolgus monkeys demonstrated linear PK and significant NK cell count reduction, which was described using PK/PD modeling. This approach may be used to guide investigative product dose selections for inflammatory diseases where NK cell count alterations are quantifiable.

Homeostasis of human NK cells is not IL-15 dependent.

IL-15 is a proinflammatory cytokine that plays an important role in the development and activation of NK cells and is a potential target for inflammatory disease therapy. Studies conducted in IL-15- and IL-15R knockout mice identified IL-15 as an important cytokine for NK cell homeostasis. Consistent with this information derived from genetically modified mice, we demonstrated that neutralizing IL-15 with a mouse anti-mouse IL-15 mAb (M96) depletes C57BL/6 mouse NK cells. An mAb directed against macaque IL-15 (Hu714MuXHu) was manufactured and demonstrated to block IL-15-induced activation of nonhuman primate (NHP) NK cells in vitro. Neutralization of macaque IL-15 by parenteral administration of Hu714MuXHu reduces (>95%) circulating NK cell counts in NHPs. A blocking mAb directed against human IL-15 (huIL-15; AMG 714) was manufactured. Unexpectedly, when human subjects were treated with the blocking anti-IL-15 Ab AMG 714 in clinical trials, no reductions in circulating NK cell counts were observed despite achieving significantly higher exposures than the levels of Hu714MuXHu needed to cause NK cell count reductions in NHPs in vivo. Both AMG 714 and Hu714MuXHu are able to block huIL-15 activity in a human T cell blast proliferation and IFN-γ production assay. Both Abs block huIL-15-mediated Stat5 activation and CD69 expression in human NK cells. Collectively, these results demonstrate that NK cell homeostasis is obligatorily dependent upon IL-15 in both mice and NHPs, but that IL-15 is dispensable for maintenance of circulating human NK cells.

Magnetic resonance imaging in rheumatoid arthritis clinical trials: emerging patterns based on recent experience.

OBJECTIVE: The current validated magnetic resonance imaging (MRI) scoring method for rheumatoid arthritis (RA) in clinical trials, RA MRI Score (RAMRIS), incorporates all metacarpophalangeal (MCP) and wrist joints except MCP-1. The experience with radiographic scoring, however, was that excluding certain bones in the wrist improved the discriminative power for changes over time. In this study, we pool MRI data from randomized controlled clinical trails (RCT) to determine which combination of MCP and wrist joints are most sensitive and discriminative for structural changes over time. METHODS: MR images from 4 multicenter RCT, including 522 RA patients, were read by 2 radiologists, using the RAMRIS scoring system for erosion, osteitis, and synovitis. In one RCT, joint-space narrowing (JSN) was assessed cross-sectionally by one radiologist using a previously validated method. Baseline frequencies of erosion, JSN, osteitis, and synovitis of different bones and joints in the hand and wrist were compared. Intraclass correlation coefficients between readers were determined for each location. Finally, 7 different combinations of bone/joint locations were compared for their ability to discriminate subjects showing increases or decreases from baseline greater than or equal to smallest detectable changes (SDC) at Weeks 12 or 24. RESULTS: Frequency of involvement and reliability for assessing change varied by location. As in earlier analyses, excluding certain wrist bones increased the percentage of subjects showing changes greater than or equal to SDC. CONCLUSION: These findings suggest that excluding wrist bones that do not frequently or reliably demonstrate structural changes improves the discriminative power of the RAMRIS scoring system.

A review of current animal models of osteoarthritis pain.

Osteoarthritis (OA) is a complex disease plagued by a significant unmet need for treatment. To date, no disease- modifying OA drugs (DMOADs) exist and the available symptom-modifying OA drugs (SMOADs) have limitations. Although a complete understanding of the mechanisms of OA pain in humans is lacking, animal models have helped provide insight into the multifaceted origin and manifestation of OA pain. Success in discovering new therapeutics will likely require reliance on good animal models. This review summarizes the animal models available for studying pain associated with OA.

Patient-reported outcomes in a randomized trial of etanercept in psoriatic arthritis.

OBJECTIVE: To evaluate the effects of etanercept treatment on patient-reported outcomes (PRO) in patients with psoriatic arthritis (PsA). METHODS: A 24-week double-blind comparison to placebo was followed by a 48-week open-label phase in which all eligible patients received etanercept. PRO were measured using the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI), the Medical Outcomes Study Short-Form (SF-36), the EQ-5D visual analog scale (VAS), and the American College of Rheumatology (ACR) patient pain assessment. RESULTS: Beginning at Week 4 and continuing through Week 24 of double-blind treatment, patients treated with etanercept had significantly higher mean percentage improvement in HAQ-DI relative to baseline than patients given placebo (53.6% vs 6.4% at Week 24; p < 0.001). After 48 weeks of open-label treatment with etanercept, the mean percentage change from study baseline was 52.8% for the original etanercept group and 46.9% for the original placebo group, with 41.2% of patients overall achieving a HAQ-DI of 0. Mean changes relative to baseline for SF-36 physical component summary scores, EQ-5D VAS, and ACR pain assessment were also significant in the double-blind period for etanercept compared with placebo (p < 0.001 for all 3 measures). Patients taking placebo achieved similar improvements once they began treatment with etanercept in the open-label period. CONCLUSION: Patients with PsA treated with etanercept reported significant improvements in physical function that were almost 10 times the improvement seen with placebo and were maintained for up to 2 years. Almost half of patients treated with etanercept reported no disability by the end of the study.

Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis.

OBJECTIVE: Osteoclast-mediated bone loss in the hand predicts future bone erosions in patients with rheumatoid arthritis (RA). Osteoclast activity depends on RANKL, which is inhibited by denosumab, an investigational fully human monoclonal antibody against RANKL. We measured metacarpal shaft cortical bone thickness using a novel computer-based technique, digital x-ray radiogrammetry (DXR), to evaluate the effects of denosumab on cortical bone in RA. METHODS: Patients (n = 227) with active, erosive RA were randomized to receive subcutaneous denosumab 60 mg or 180 mg or placebo every 6 months. All patients received stable doses of methotrexate and daily calcium and vitamin D. For this blinded post hoc analysis (n = 218), cortical bone loss was determined by DXR using computer-assisted measurement of cortical thickness and shaft width at 21 midshaft levels of the second through fourth metacarpal bones of both hands. RESULTS: At 12 months, patients receiving denosumab had significantly less metacarpal bone loss versus placebo (denosumab 60 mg: -0.0034, denosumab 180 mg: 0.0001 gain, placebo: -0.0108; P < or = 0.01 for both denosumab doses). Twelve-month decreases from baseline greater than the smallest detectable change occurred in 2 patients in the denosumab 180 mg group, 9 patients in the denosumab 60 mg group, and 12 patients in the placebo group. Negative correlation was significant between static cortical thickness ratios and static erosion scores (6 and 12 months), and for placebo, between changes in erosion scores and changes in cortical thickness ratio. CONCLUSION: Twice-yearly injections of denosumab with ongoing methotrexate treatment significantly reduced cortical bone loss in RA patients for up to 12 months. These results add to the growing evidence supporting the clinical utility of DXR.

Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates.

OBJECTIVES: To report results of subgroup analyses of bone mineral density (BMD) and bone turnover markers from a randomised, double-blind, placebo-controlled, phase II study of denosumab, an investigational RANKL inhibitor, in patients with rheumatoid arthritis (RA) concurrently receiving treatment with bisphosphonates or glucocorticoids. METHODS: Patients received subcutaneous placebo (n=75), denosumab 60 mg (n=71) or denosumab 180 mg (n=72) at baseline and 6 months. Assessments included dual x-ray absorptiometry scans of the lumbar spine and hip, and determination of levels of serum type I C-telopeptide (sCTx-I) and serum procollagen 1N-terminal peptide (P1NP). RESULTS: Denosumab treatment increased mean lumbar spine and hip BMD and reduced sCTx-I and P1NP compared with placebo through 12 months, regardless of baseline BMD or marker levels or concomitant bisphosphonate or glucocorticoid use. CONCLUSIONS: This study extends evidence that denosumab increases BMD and reduces bone turnover in patients with RA and may provide a new therapeutic option for reducing systemic bone loss in patients with RA.

Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial.

OBJECTIVE: RANKL is essential for osteoclast development, activation, and survival. Denosumab is a fully human monoclonal IgG2 antibody that binds RANKL, inhibiting its activity. The aim of this multicenter, randomized, double-blind, placebo-controlled, phase II study was to evaluate the effects of denosumab on structural damage in patients with rheumatoid arthritis (RA) receiving methotrexate treatment. METHODS: RA patients received subcutaneous placebo (n = 75), denosumab 60 mg (n = 71), or denosumab 180 mg (n = 72) injections every 6 months for 12 months. The primary end point was the change from baseline in the magnetic resonance imaging (MRI) erosion score at 6 months. RESULTS: At 6 months, the increase in the MRI erosion score from baseline was lower in the 60-mg denosumab group (mean change 0.13; P = 0.118) and significantly lower in the 180-mg denosumab group (mean change 0.06; P = 0.007) than in the placebo group (mean change 1.75). A significant difference in the modified Sharp erosion score was observed as early as 6 months in the 180-mg denosumab group (P = 0.019) as compared with placebo, and at 12 months, both the 60-mg (P = 0.012) and the 180-mg (P = 0.007) denosumab groups were significantly different from the placebo group. Denosumab caused sustained suppression of markers of bone turnover. There was no evidence of an effect of denosumab on joint space narrowing or on measures of RA disease activity. Rates of adverse events were comparable between the denosumab and placebo groups. CONCLUSION: Addition of twice-yearly injections of denosumab to ongoing methotrexate treatment inhibited structural damage in patients with RA for up to 12 months, with no increase in the rates of adverse events as compared with placebo.

Rapid and sustained improvement in health-related quality of life and utility for 72 weeks in patients with ankylosing spondylitis receiving etanercept.

OBJECTIVE: To examine the longterm effect of etanercept (ETN) therapy on health-related quality of life (HRQOL) and utility in patients with ankylosing spondylitis. METHODS: Patients completing a 24-week placebo-controlled trial were continued on ETN in a 72-week open-label extension study. Short Form-36 (SF-36), EuroQOL-5D (EQ-5D), and EuroQOL visual analog scale (EQ-VAS) scores were collected at open-label baseline and every 12 weeks thereafter. Mental and physical component scores (MCS and PCS) of the SF-36, EQ-5D and SF-6D utility scores, and quality-adjusted life-years (QALY) were calculated. RESULTS: 257 patients [129 previous placebo (PLA) and 128 ETN recipients] enrolled in this open-label extension study, and 85% completed the 72-week followup. PCS, EQ-5D and SF-6D utilities, and EQ-VAS were significantly lower at open-label baseline in the previous PLA group (PLA/ETN group) than in the previous ETN group (ETN/ETN group; all p < 0.001). At week 12, PCS and MCS, EQ-5D and SF-6D utility scores, and EQ-VAS were similar in the PLA/ETN and ETN/ETN groups. As expected, mean change in EQ-5D in the PLA/ETN group was significantly greater than that for SF-6D (0.18 vs 0.06; p < 0.0001). HRQOL and utility improvements were maintained in both groups for up to 72 weeks. The average 72-week QALY gain per person in the PLA/ETN group was 0.24 and 0.10 for EQ-5D and SF-6D, respectively. CONCLUSION: Patients continuing ETN therapy sustained HRQOL and utility improvements attained during the original PLA-controlled trial. Patients previously taking PLA showed rapid and sustained improvements in HRQOL and utility and substantial QALY gain with ETN therapy.

Standardizing assessment and reporting of adverse effects in rheumatology clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0.

OBJECTIVE: The OMERACT Drug Safety Working Group focuses on standardization of assessment and reporting of adverse events in clinical trials and longitudinal and observational studies in rheumatology. This group developed the Rheumatology Common Toxicity Criteria (RCTC) in 1999, building on the Oncology Common Toxicity Criteria. At OMERACT 8, a workshop group reviewed the use of the RCTC and other instruments in rheumatology clinical trials to date, to revise and to stimulate its implementation. METHODS: The Working Group drafted a revision of the RCTC after an iterative examination of its contents, terms, and definitions. The RCTC were compared with the Oncology Common Toxicity Criteria (CTC v.2.0), and the Common Terminology Criteria for Adverse Events (CTCAE v.3.0). In addition a pharmaceutical company focus group met to clarify the challenges of application of RCTC terms and definitions, relative to the standard in pharmaceutical clinical trials, i.e., verbatim recording of adverse events followed by mapping to Medical Dictionary of Drug Regulatory Activities (MedDRA) terms. The workshop focused on the proposed revision of RCTC to version 2.0 and on the research agenda, including a validation of the RCTC in future trials. RESULTS: At OMERACT 8, breakout groups amended the contents of the 4 current and 2 new categories of adverse event terms within the draft RCTC v.2.0. Participants recognized the need to standardize the definitions for disease flares, infection, malignancy, and certain syndromes such as drug hypersensitivity and infusion reactions. Moderate consensus (62%) was reached in the final plenary session that the amended RCTC v.2.0 should be promulgated and tested in available trials of anti-tumor necrosis factor agents. CONCLUSION: The RCTC has face validity and construct validity. However, documentation of discrimination and feasibility (the other elements of the OMERACT filter) is needed. Collaboration with drug safety working groups in rheumatology professional organizations is necessary to enable this project.

A placebo-controlled, randomized, double-blinded study evaluating the safety of etanercept in patients with rheumatoid arthritis and concomitant comorbid diseases.

OBJECTIVE: To evaluate the safety of etanercept in patients with rheumatoid arthritis (RA) and concomitant comorbidities. METHODS: The safety of etanercept (25 mg twice weekly) in RA patients with at least one comorbidity (i.e. diabetes mellitus, chronic pulmonary disease, recent pneumonia, recurrent infections) was evaluated in a 16-week placebo-controlled, randomized, double-blinded study. The primary endpoint was the incidence of medically important infections (MIIs; defined as those resulting in hospitalization or treatment with intravenous antibiotics). RESULTS: Data from 535 patients were analysed; the study was terminated early because of slow enrolment and lower than predicted incidence of infections. Serious adverse events (5.9% placebo, 8.6% etanercept) were most commonly observed in the cardiovascular system. Six patients (1 placebo; 5 etanercept) died during the study; four deaths were attributed to cardiovascular events. The numerically higher mortality in the etanercept group was not statistically significant [relative risk (95% CI) = 5.06 (0.59, 42.99)] but remains unexplained. No etanercept-related increase in the incidence of MIIs (3.7% placebo, 3.0% etanercept) or overall infections was observed in the total study population or in subgroups of patients who were > or = 65 yrs of age, had diabetes or had chronic pulmonary disease. CONCLUSIONS: Etanercept was generally well tolerated by RA patients with comorbidities. Serious adverse events and deaths occurred more frequently in the etanercept group but event numbers were small and CIs were broad, preventing reliable conclusions from being drawn. Although the study had limited statistical power, the incidence of MIIs in these patients was not increased by etanercept treatment.

Assessing single joints in arthritis clinical trials.

Endpoints and outcome measurements to detect changes in joint structure for the assessment of single joints are needed to enable rheumatology clinical trials of therapies targeting preservation of joint structure, especially via locally applied therapies. While the assessment of certain aspects of single joint inflammation and function is accepted in the evaluation of osteoarthritis (OA) using the WOMAC, it tends to be limited to the knee and hip. The advent of therapies that are directed toward a single joint in inflammatory arthritis, including intraarticular cytokine antagonists and gene therapeutics, requires reliable measures to assess change over time in single joints and the clinical meaningfulness of such change. Traditionally, clinical trials for inflammatory arthritis have used composite response indices such as American College of Rheumatology response or improvement in Disease Activity Score as outcomes based on multiple joint clinical measures, acute phase reactants, and functional status. However, it is not known whether these will appropriately detect changes referable to single joint intervention. This Special Interest Group was developed to bring together interested individuals to identify and evaluate outcome measurements for single joints. The knee was the initial focus, as clinical, radiographic, and functional assessments have been well developed for knee OA. A PubMed English language review was conducted before OMERACT 8, evaluating existing clinical instruments in the context of the OMERACT filter. At OMERACT 8, the group developed a research agenda to perform additional validation studies of clinical and functional indices, imaging, synovial histopathology, and soluble biomarkers.

Bone erosions and bone marrow edema as defined by magnetic resonance imaging reflect true bone marrow inflammation in rheumatoid arthritis.

OBJECTIVE: To investigate the pathologic nature of features termed "bone erosion" and "bone marrow edema" (also called "osteitis) on magnetic resonance imaging (MRI) scans of joints affected by rheumatoid arthritis (RA). METHODS: RA patients scheduled for joint replacement surgery (metacarpophalangeal or proximal interphalangeal joints) underwent MRI on the day before surgery. The presence and localization of bone erosions and bone marrow edema as evidenced by MRI (MRI bone erosions and MRI bone marrow edema) were documented in each joint (n=12 joints). After surgery, sequential sections from throughout the whole joint were analyzed histologically for bone marrow changes, and these results were correlated with the MRI findings. RESULTS: MRI bone erosion was recorded based on bone marrow inflammation adjacent to a site of cortical bone penetration. Inflammation was recorded based on either invading synovial tissue (pannus), formation of lymphocytic aggregates, or increased vascularity. Fat-rich bone marrow was replaced by inflammatory tissue, increasing water content, which appears as bright signal enhancement on STIR MRI sequences. MRI bone marrow edema was recorded based on the finding of inflammatory infiltrates, which were less dense than those of MRI bone erosions and localized more centrally in the joint. These lesions were either isolated or found in contact with MRI bone erosions. CONCLUSION: MRI bone erosions and MRI bone marrow edema are due to the formation of inflammatory infiltrates in the bone marrow of patients with RA. This emphasizes the value of MRI in sensitively detecting inflammatory tissue in the bone marrow and demonstrates that the inflammatory process extends to the bone marrow cavity, which is an additional target structure for antiinflammatory therapy.

Continued inhibition of radiographic progression in patients with psoriatic arthritis following 2 years of treatment with etanercept.

OBJECTIVE: Clinical and radiographic responses were evaluated in patients with psoriatic arthritis (PsA) treated for up to 2 years with etanercept. METHODS: Patients were previously randomized to receive placebo or etanercept in a double-blind study and chose to participate in the current open-label extension phase. All patients received etanercept 25 mg twice weekly. Radiographic progression was determined at baseline, 1 year, and 2 years using the Sharp method modified to include joints frequently affected in PsA. Arthritis and psoriasis responses were determined using American College of Rheumatology 20% (ACR20) improvement criteria, PsA response criteria (PsARC), and the psoriasis area severity index (PASI). RESULTS: Of 205 patients randomized, 169 entered open-label, and 141 [71 randomized to receive placebo (placebo/etanercept) and 70 randomized to receive etanercept (etanercept/etanercept)] had radiographic data available for analysis at 2 years. ACR20 criteria, PsARC, and PASI 50 criteria were met by 64%, 84%, and 62%, respectively, of etanercept/etanercept patients at the end of the 48-week open-label period. Placebo/etanercept patients achieved comparable results within 12 weeks that were sustained at 48 weeks (63%, 80%, and 73%). Radiographic progression was inhibited in the etanercept/ etanercept patients (mean adjusted change in total Sharp score of -0.38 from baseline to 2 yrs). In placebo/etanercept patients, disease progression was inhibited once patients began receiving etanercept (mean adjusted change of -0.22 from 1 year to 2 years). Adverse event rates were similar to those observed during randomized phase, with only one serious adverse event deemed possibly related to etanercept. CONCLUSION: These data demonstrate a sustained benefit of etanercept treatment, including inhibition of radiographic progression, in patients with PsA.