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Background and Purpose AMG 139 is a human anti-IL-23 antibody currently in a phase II trial for treating Crohn's disease. To support its clinical development in humans, in vitro assays and in vivo studies were conducted in cynomolgus monkeys to determine the pharmacology, preclinical characteristics and safety of this monoclonal antibody. Experimental Approach The in vitro pharmacology, pharmacokinetics (PK), pharmacodynamics and toxicology of AMG 139, after single or weekly i.v. or s.c. administration for up to 26 weeks, were evaluated in cynomolgus monkeys. Key Results AMG 139 bound with high affinity to both human and cynomolgus monkey IL-23 and specifically neutralized the biological activity of IL-23 without binding or blocking IL-12. After a single dose, linear PK with s.c. bioavailability of 81% and mean half-life of 8.4–13 days were observed. After weekly s.c. dosing for 3 or 6 months, AMG 139 exposure increased approximately dose-proportionally from 30 to 300 mg·kg−1 and mean accumulation between the first and last dose ranged from 2- to 3.5-fold. Peripheral blood immunophenotyping, T-cell-dependent antigen responses and bone formation markers were not different between AMG 139 and vehicle treatment. No adverse clinical signs, effects on body weight, vital signs, ophthalmic parameters, clinical pathology, ECG, organ weights or histopathology were observed in the monkeys with the highest dose of AMG 139 tested (300 mg·kg−1 s.c. or i.v.). Conclusions and Implications The in vitro pharmacology, PK, immunogenicity and safety characteristics of AMG 139 in cynomolgus monkeys support its continued clinical development for the treatment of various inflammatory diseases.

Background Blockade of inducible costimulatory ligand (ICOSL) might be a promising approach for autoimmune diseases such as systemic lupus erythematosus (SLE). We evaluated AMG 557, an anti-ICOSL monoclonal antibody, in an exploratory phase 1b study of SLE subjects with inflammatory arthritis, by withdrawing background therapies to improve interpretability of a small study. Objectives To investigate potential efficacy, safety, and tolerability of AMG 557 in subjects with lupus arthritis. Methods This double-blind, randomized, placebo-controlled trial enrolled subjects with SLE and active lupus arthritis (≥4 tender and 4 swollen joints) and Systemic Lupus Erythematosus Disease Activity Index [SLEDAI] score ≥6 despite stable background immunosuppressants. Upon enrollment, investigators were permitted to use up to 20 mg/day of prednisone, which was tapered by day 85 to 7.5 mg/day or 50% of baseline, whichever was lower. Subjects received AMG 557 210 mg or placebo once weekly for 3 weeks followed by 10 additional doses every other week until day 155. At day 29, background immunosuppressants were withdrawn. The primary clinical endpoint was a composite Lupus Arthritis Responder Index at day 169; response was defined as achieving: (1) 50% decrease in combined tender and swollen joint counts, and (2) ≥1 letter improvement in the musculoskeletal subsystem of the British Isles Lupus Assessment Group (BILAG) index and (3) prespecified immunosuppressant medication withdrawal and/or prednisone taper. Safety was a co-primary endpoint. Exploratory endpoints included safety, 4-point reduction of SLEDAI, clinical indices (SLEDAI, BILAG), complement components, autoantibodies, and lymphocyte populations. Results Twenty subjects (19 females) were randomized (10 AMG 557, 10 placebo) at 8 sites in North America, Asia, and Europe. The primary endpoint was met by 3/10 subjects receiving AMG 557 and 1/10 subjects receiving placebo ( P =ns). A 4-point decrease in SLEDAI score was achieved by 7/10 subjects on AMG 557 and 2/10 subjects on placebo. At day 169, subjects receiving AMG 557 had decreases from baseline in mean global BILAG and SLEDAI scores of 36% and 48% respectively, compared to 25% and 11% in subjects receiving placebo. Lupus-associated biomarkers, including serum complement indices (C3, C4, and CH50), and autoantibodies, including anti-dsDNA, demonstrated trends towards improvement relative to placebo. Treatment-emergent adverse events (AEs) were similar between placebo and AMG 557 arms; most commonly headache and upper respiratory tract infection. Conclusions Results from this exploratory placebo-controlled trial in lupus arthritis suggest potential clinical benefit of ICOSL blockade by AMG 557. These data support further clinical trials intervening in this costimulatory pathway in SLE and other autoimmune diseases. Disclosure of Interest L. Cheng Shareholder of: Amgen Inc., Employee of: Amgen Inc., Z. Amoura Consultant for: GlaxoSmithKline, AstaZeneca, BristolMyerSquibb, Amgen Inc., B. Cheah Grant/research support from: Merck, F. Hiepe Grant/research support from: Sanofi, Amgen Inc., GlaxoSmithKline, AstaZeneca, Ablynx, Consultant for: Baxalta, AstaZeneca, BristolMyerSquibb, GlaxoSmithKline, Novartix, Miltenyi, Neovacs, Hexal, Neovi, Speakers bureau: Pfizer Inc., Roche, UCB, B. Sullivan Shareholder of: Amgen Inc., Employee of: Amgen Inc., L. Zhou Shareholder of: Amgen Inc., Employee of: Amgen Inc., G. Arnold Shareholder of: Amgen Inc., Employee of: Amgen Inc., W. Tsuji Shareholder of: Amgen Inc., JohnsonJ Partner in the Cascadia Drug Development Group, J. Merrill Consultant for: EMD Serono, BristolMyerSquibb, Human Genome Sciences, UCB, AstraZeneca, Celgene, J. Chung Shareholder of: Amgen Inc., Employee of: Amgen Inc.

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.

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.

Objective Periarticular osteoporosis is one of the earliest radiographic signs of bone damage in rheumatoid arthritis (RA). Denosumab, an investigational fully human monoclonal antibody that binds to RANKL, inhibits bone erosion and systemic bone loss in clinical studies of patients with RA. In this hand bone mineral density (BMD) substudy, we investigated the effects of denosumab on hand BMD and its correlation with hand erosion scores. Methods Patients receiving methotrexate for erosive RA were randomized in a 1:1:1 ratio to receive subcutaneous placebo, denosumab 60 mg, or denosumab 180 mg at 0 and 6 months. Measurements included BMD (by dual x-ray absorptiometry [DXA]) of both hands (0, 1, 6, and 12 months), magnetic resonance images of the hands/wrists (0 and 6 months), and radiographs of the hands/wrists and feet (0, 6, and 12 months). Results There were 56 patients (13 placebo, 21 denosumab 60 mg, and 22 denosumab 180 mg). Mean changes in hand BMD at 6 and 12 months were: +0.8% and +1.0%, respectively, for denosumab 60 mg; +2.0% and +2.5%, respectively, for denosumab 180 mg; and −1.2% and −2.0%, respectively, for placebo. Erosion scores remained near baseline in the denosumab groups and increased from baseline in the placebo group. A negative correlation was observed between hand BMD and erosion scores. Conclusion In patients with RA, denosumab provided protection against erosion, and not only prevented bone loss but increased hand BMD as measured by DXA.

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.

The need to develop validated outcome measures to assess response to therapies in single joints has been recognized. In 2004, a task force was established to assess established and novel outcome measures in accordance with the OMERACT filter (truth, discrimination, and feasibility) for single joint assessment. This report describes the proceedings of the single joint assessment special interest group (SIG) at OMERACT 9, including an updated literature review of imaging of the knee joints, with a focus on the extent to which these modalities fulfill the OMERACT filter. A series of studies are reported that examine patient reported, clinical examination, and imaging outcomes in therapeutic studies in knee arthritis. A summary of discussions from the meeting are presented that raise many of the ongoing challenges in establishing appropriate domains to evaluate a range of conditions and potential therapeutic interventions. Because of emerging drug candidates and modalities targeting individual joints, the ongoing work of this SIG is providing the evidence base that can be used to establish a core domain set to incorporate as outcomes in future studies.

Objective To investigate the effect of etanercept therapy on radiographic progression in patients with ankylosing spondylitis (AS). Methods Patients with AS who had previously participated in a 24-week randomized, double-blind, placebo-controlled trial of etanercept therapy were enrolled in a 72-week open-label extension. Radiographs of the cervical and lumbar spine from patients who received etanercept (25 mg twice weekly) for up to 96 weeks were compared with radiographs from patients in a large prevalence cohort (Outcome Assessments in Ankylosing Spondylitis International Study [OASIS]) who had not been treated with anti–tumor necrosis factor α (anti-TNFα) agents. Radiographs obtained at 2 time points up to 96 weeks apart from patients in both study populations were digitized and read by 2 independent readers who were blinded with regard to patient group and sequence. The primary end point was the 96-week change in the modified Stoke AS Spine Score (mSASSS). Results A total of 257 patients treated with etanercept were compared with 175 unselected patients from the OASIS study. There was no significant difference in the change in the mSASSS from baseline among patients who received etanercept (mean ± SD 0.91 ± 2.45) versus those from the OASIS group (0.95 ± 3.18). Conclusion Unlike other inflammatory rheumatic diseases such as rheumatoid arthritis and psoriatic arthritis, structural progression in AS seems to be independent of TNF, despite the fact that TNF is responsible for the signs and symptoms due to inflammation in this disease.

Objective: Evaluate long-term safety and efficacy of etanercept treatment in patients with ankylosing spondylitis (AS). Methods: Patients with AS who previously participated in a randomised controlled trial (RCT) of etanercept were eligible to enrol in a 168-week open-label extension (OLE). Safety end points included rates of adverse events (AE), serious adverse events (SAE), infections, serious infections and death. Efficacy end points included Assessment in Ankylosing Spondylitis (ASAS20) response, ASAS 5/6 response and partial remission rates. Results: A total of 257 of 277 patients (92%) enrolled in the OLE. After up to 192 weeks of treatment with etanercept, the most common AEs were injection site reactions, headaches and diarrhoea. The exposureadjusted rate of SAEs was 0.08 per patient-year. The rate of infections was 1.1 per patient-year, and the rate for serious infections was 0.02 per patient-year. No deaths were reported. Of patients who received etanercept in both the RCT and OLE and were still in the trial, 71% were ASAS20 responders at week 96, and 81% were responders at week 192. ASAS 5/6 response rates were 61% at week 96 and 60% at week 144, and partial remission response rates were 41% at week 96 and 44% at week 192. Placebo patients who switched to etanercept in the OLE showed similar patterns of efficacy maintenance. Conclusions: Etanercept was well tolerated for up to 192 weeks in patients with AS, with no unexpected AEs or SAEs observed. No deaths were reported. Improvements in the signs and symptoms of AS were maintained for up to 192 weeks.

To assess spinal inflammation by magnetic resonance imaging (MRI) before and after treatment with the tumor necrosis factor receptor fusion protein etanercept compared with placebo.As part of a recently published randomized, controlled trial, 40 patients with ankylosing spondylitis (AS) underwent MRI of the lower thoracic and lumbar spine at 4 different time points: baseline, 12 weeks, 24 weeks, and 48 weeks. Nineteen patients received subcutaneous etanercept twice weekly (25 mg twice daily) for 1 year, and 21 patients received placebo for 6 months before being switched to etanercept. The mean age of the patients was 39.7 years, 75% were male, 89% were HLA-B27 positive, and the mean disease duration was 13 years. MRI examinations included T1-weighted sequences before and after application of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) and T2-weighted fat-saturated sequences. MRI sequences were scored with an adjusted AS spinal MRI score, using predefined vertebral units (VUs) as a basis.After 12 weeks, spinal inflammation (as assessed by T2-weighted MRI with fat saturation) regressed by 54% in the etanercept group (mean score 1.33 per VU at baseline and 0.61 per VU at 12 weeks; P = 0.002) but worsened by 13% in the placebo group (0.94 at baseline and 1.06 at 12 weeks) (P0.001 between groups). After switching to etanercept, placebo patients improved similarly. T1-weighted Gd-DTPA MRI sequences performed equally well in detecting spinal changes. At baseline,50% of all active lesions were detected in the thoracic spine. Deterioration of chronic changes was significant only in patients treated with placebo.Etanercept treatment of patients with active AS results in regression of spinal inflammation as assessed by spinal MRI. Inclusion of the thoracic spine in MRI examinations of patients with AS may be of particular importance.

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.

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.

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 ≤ 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.

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.

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.

To examine the longterm effect of etanercept (ETN) therapy on health-related quality of life (HRQOL) and utility in patients with ankylosing spondylitis.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.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 p0.001). 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; p0.0001). 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.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.

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.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.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.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.

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.

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.

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.

Clinical and radiographic responses were evaluated in patients with psoriatic arthritis (PsA) treated for up to 2 years with etanercept.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).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.These data demonstrate a sustained benefit of etanercept treatment, including inhibition of radiographic progression, in patients with PsA.

Objective: To evaluate the continued safety and durability of clinical response in patients with ankylosing spondylitis receiving etanercept. Methods: 277 patients who had participated in a previous randomised, double blind, placebo controlled 24 week trial were eligible to continue in this open label extension study. All patients who enrolled in the open label extension (n = 257) received subcutaneous etanercept 25 mg twice weekly for up to 72 weeks, for a combined 96 weeks of cumulative trial and open label experience. For the patients who had received etanercept for 24 weeks in the double blind trial, this represented almost 2 years of continuous etanercept treatment. Results: Patients continuing etanercept treatment had a sustained response for almost 2 years, with 74% achieving an ASsessments in Ankylosing Spondylitis 20% (ASAS 20) response after 96 weeks of etanercept treatment. Patients who had received placebo in the preceding double blind trial had similar responses, with 70% of patients attaining an ASAS 20 response after 24 weeks of etanercept treatment and 78% achieving an ASAS 20 response after 72 weeks. Improved spinal mobility was seen in both groups. Etanercept was well tolerated in patients treated for up to 96 weeks. Conclusion: The subcutaneous administration of twice weekly doses of etanercept provided sustained durability of response in the improvement of signs and symptoms of ankylosing spondylitis for nearly 2 years.

Objective To determine the safety and efficacy of etanercept in a multicenter, randomized, placebo-controlled, double-blind trial of adults with moderate to severe active ankylosing spondylitis (AS). Methods Patients (n = 277) were treated with either etanercept 25 mg (n = 138) or placebo (n = 139) subcutaneously twice weekly for 24 weeks. The primary outcome measures were the percentages of patients achieving the Assessments in Ankylosing Spondylitis 20% response (ASAS20) at weeks 12 and 24. Other outcome measures included the percentage of patients achieving higher ASAS responses, and the safety of etanercept in patients with AS. All outcome measures were assessed at 2, 4, 8, 12, and 24 weeks. Results Treatment with etanercept resulted in dramatic improvement. The ASAS20 was achieved by 59% of patients in the etanercept group and by 28% of patients in the placebo group (P < 0.0001) at week 12, and by 57% and 22% of patients, respectively, at week 24 (P < 0.0001). All individual ASAS components, acute-phase reactant levels, and spinal mobility measures were also significantly improved. The safety profile of etanercept was similar to that reported in studies of patients with rheumatoid arthritis or psoriatic arthritis. The only adverse events that occurred significantly more often in the etanercept group were injection-site reactions, accidental injuries, and upper respiratory tract infections. Conclusion Etanercept is a highly effective and well tolerated treatment in patients with active AS.