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Background Certolizumab pegol (CZP) treatment has been shown to significantly improve work and household productivity and social participation compared to placebo in active non-radiographic axial spondyloarthritis (nr-axSpA) patients up to 24 weeks. Here, we report the impact of CZP in combination with non-biologic background medication (NBBM) on signs and symptoms of nr-axSpA compared to placebo+NBBM. Methods C-axSpAnd (NCT02552212) is a 3-year, phase 3, multicentre study including a 52-week double-blind, placebo-controlled period (completed). Patients had active nr-axSpA, objective signs of inflammation (OSI; elevated CRP and/or positive MRI of the sacroiliac joint), previous inadequate response to ≥ 2 NSAIDs and were randomised 1:1 to CZP (400 mg at Weeks 0/2/4, then 200 mg every 2 weeks) or placebo. The validated arthritis-specific Work Productivity Survey (WPS) assessed the impact of nr-axSpA on work and household productivity and social participation. Missing data were imputed using last observation carried forward (LOCF) post hoc in the Full Analysis Set (randomised patients who received ≥1 dose of CZP). Results 317 patients were randomised (CZP: 159; placebo: 158). Mean age at baseline was 37.3 years and 51.4% of patients were female. At baseline, most patients were employed (CZP: 124 [77.8%]; placebo: 123 [78.0%]) and reported a mean 3.7 (CZP) and 3.5 (placebo) workdays missed per month due to disease (Table 1). By Week 12, work absenteeism substantially improved in the CZP group compared with placebo (0.9 vs 2.1 days missed per month, LOCF), with further improvements at Week 52 (0.3 vs 2.0 days missed per month, LOCF). Between Week 12 and Week 52, most placebo patients (104, 65.8%) switched to open-label CZP, impacting Week 52 imputed outcomes. Despite this, similar patterns of improvement following CZP treatment were seen for absenteeism, workdays with impaired productivity, household days with missed/reduced productivity and social participation between imputed and observed case data (Table 1). Improvements were similar between male and female patients (data not shown). Conclusion CZP treatment resulted in improvements in work and household productivity and social participation for nr-axSpA patients as early as Week 12 compared to background medication only, with benefits maintained to Week 52. Disclosures K. Gaffney: Other; Research Grants/Consultancy Fees from Abbvie, Biogen, Celgene, Gilead, Izana, Janssen, Lilly, Novartis, Pfizer, UCB Pharma. A. Deodhar: Consultancies; AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Glaxo Smith and Klein, Janssen, Novartis, Pfizer and UCB. Grants/research support; BMS, Eli Lilly, Glaxo Smith & Kline, Janssen, Novartis, Pfizer and UCB. L. Gensler: Consultancies; Galapagos, Eli Lilly and Janssen. Grants/research support; AbbVie, Amgen, Novartis, UCB Pharma. J. Kay: Consultancies; AbbVie, Boehringer Ingelheim, Celltrion Healthcare, Horizon Therapeutics, Merck Sharp & Dohme, MorphoSys, Novartis, Pfizer, Samsung Bioepis, Sandoz and UCB Pharma. Grants/research support; Gilead Sciences, Novartis AG, Pfizer and UCB Pharma. W. Maksymowych: Other; Consultant and/or speaker fees and/or grants from AbbVie, Amgen, Eli Lilly, Janssen, Merck, Pfizer, Synarc, Sanofi and UCB Pharma. N. Haroon: Consultancies; Abbvie, Amgen, Eli Lilly, Janssen, Novartis and UCB Pharma. R. Landewé: Consultancies; Abbott, Ablynx, Amgen, Astra-Zeneca, Bristol Myers Squibb, Centocor, GlaxoSmithKline, Novartis, Merck, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth. Member of speakers’ bureau; Abbott, Amgen, Bristol Myers Squibb, Centocor, Merck, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth. Grants/research support; Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth. M. Rudwaleit: Consultancies; Abbott, Bristol-Myers Squibb, Janssen, MSD, Pfizer, Roche, UCB Pharma. S. Hall: Other; Consulting fees/ research grants from AbbVie, Eli Lilly, Novartis, and UCB Pharma. L. Bauer: Other; Employee of UCB Pharma. B. Hoepken: Other; Employee of UCB Pharma. N. de Peyrecave: Other; Employee of UCB Pharma. T. Kumke: Other; Employee of UCB Pharma. D. van der Heijde: Consultancies; AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB. Other; Director of Imaging Rheumatology BV.

There are now eight approved biological disease-modifying antirheumatic drugs (bDMARDs), two biosimilars and one targeted synthetic DMARD in Australia with a number of new products and biosimilars in the pipeline. bDMARDs have excellent efficacy, especially when combined with traditional DMARDs, and a well characterised but manageable safety profile. These expanded therapeutic options have revolutionised patient care and made remission (including drug free remission) a realistic goal. Evidence of a "window of opportunity" that changes the long term phenotype of the disease has been well established, so therapy should be commenced as early as possible in the disease process and a shared care model between general practitioner and rheumatologist provides the best outcomes. While there is no cure for rheumatoid arthritis, treatment has improved to the point where many patients can achieve a normal quality of life.

[Tahir, Hasan] Barts Hlth NHS Trust, Rheumatol, London, England. [Mease, Philip J.] Swedish Med Ctr, Dermatol, Seattle, WA USA. [Mease, Philip J.] Univ Washington, Seattle, WA 98195 USA. [Kavanaugh, Arthur] Univ Calif La Jolla, San Diego Sch Med, La Jolla, CA USA. [Reimold, Andreas] Dallas Vet Affairs Med Ctr, Dallas, TX USA. [Reimold, Andreas] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Rech, Juergen] Friedrich Alexander Univ Erlangen Nurnberg, Univ Klinikum Erlangen, Dept Internal Med Rheumatol & Immunol, Erlangen, Germany. [Hall, Stephen] Emeritus Res, Rheumatol, Camberwell, Australia. [Geusens, Piet] Univ Hasselt, Rheumatol, Hasselt, Belgium. [Pellet, Pascale; Mpofu, Shephard] Novartis Pharma AG, Immunol & Dermatol, Basel, Switzerland. [Delicha, Eumorphia Maria] Novartis Pharma AG, Biostat, Basel, Switzerland. [Pricop, Luminita] Novartis Pharmaceut, Immunol Hepatol & Dermatol Franchise, E Hanover, NJ USA.

Background:Upadacitinib (UPA) 15 mg once daily (QD) has demonstrated efficacy in phase 3 studies of patients with rheumatoid arthritis (RA).1–4 Early prediction of response to treatment with UPA could help to optimize therapy.Objectives:To identify baseline (BL) characteristics or Week (Wk) 12 disease activity measures that may predict the achievement of remission (REM) or low disease activity (LDA) at 6 months in patients with RA receiving UPA 15 mg.Methods:This ad hoc analysis included patients who were randomized to UPA 15 mg QD, as monotherapy in methotrexate (MTX)-naïve patients (SELECT-EARLY) or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), in patients with an inadequate response (IR) to MTX (SELECT-COMPARE) or ≥1 tumor necrosis factor inhibitors (TNFis) (SELECT-BEYOND and SELECT-CHOICE). The association of BL characteristics (including age, disease duration, prior/concomitant treatments, C-reactive protein [CRP], seropositivity, and disease activity) and Wk 12 disease activity parameters with the achievement of Clinical Disease Activity Index (CDAI) REM (≤2.8) or LDA (≤10) at Wk 24 (or Wk 26 in SELECT-COMPARE) was assessed by concordance statistics (C-statistics), or area under the receiver operator characteristic curve. C-index values and 95% confidence intervals were calculated by fitting a univariate logistic regression model for: demographic and BL characteristics, Wk 12 disease activity measures, and change from BL at Wk 12 in disease activity measures. A multivariate logistic regression with stepwise model selection was also performed. The proportion of patients achieving Wk 24/26 CDAI REM/LDA was stratified by ≥50% improvement from BL in swollen and/or tender joint count in 66/68 joints (SJC66/TJC68).Results:A total of 1377 patients were included in the analysis. Across the 4 studies, CDAI REM and LDA were achieved in 11.0–28.4% and 50.0–58.6% of patients, respectively (Table 1). BL demographics and disease characteristics were weakly predictive (C-index 0.80) of Wk 24/26 CDAI REM or LDA. Disease Activity Score in 28 joints using CRP and pain at Wk 12 were strongly predictive of Wk 24/26 CDAI REM (except in SELECT-CHOICE). Physician’s global assessment at Wk 12 was the only common predictor in the multivariate regression models for CDAI REM/LDA at Wk 24/26 across the 4 studies. A greater proportion of patients achieving ≥50% improvement in SJC66 and TJC68 at Wk 12 achieved CDAI REM (16.5–37.8% vs 0–9.4%) or LDA (66.0–72.8% vs 20.9–35.7%) at Wk 24/26 than those who did not.Table 1.Achievement of CDAI LDA and REM at Wk 24/26aSELECT-EARLYSELECT-COMPARESELECT-BEYONDSELECT-CHOICEPatient populationMTX-naïveMTX-IRTNFi-IRTNFi-IRTreatmentUPA 15 mg monotherapy (n=317)UPA 15 mg + MTX(n=651)UPA 15 mg + csDMARD(n=146)UPA 15 mg + csDMARD(n=263)Efficacy at Wk 24/26a, n (%)CDAI REM (≤2.8)90 (28.4)150 (23.0)16 (11.0)60 (22.8)CDAI LDA (≤10)178 (56.2)343 (52.7)73 (50.0)154 (58.6)a Wk 26 for SELECT-COMPARE onlyConclusion:BL characteristics did not strongly predict response to UPA, but composite disease activity scores at Wk 12 predicted Wk 24/26 REM/LDA with UPA 15 mg QD across MTX-naïve, MTX-IR, and TNFi-IR patients. ≥50% improvement in SJC/TJC at Wk 12 was also associated with Wk 24/26 REM/LDA.References:[1]van Vollenhoven R, et al. Arthritis Rheumatol 2020;72:1607–20; 2. Genovese MC, et al. Lancet 2018;391:2513–24; 3. Fleischmann R, et al. Arthritis Rheumatol 2019;71:1788–800; 4. Rubbert-Roth A, et al. N Engl J Med 2020;383:1511–21.Acknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Laura Chalmers, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Arthur Kavanaugh Consultant of: Janssen, Grant/research support from: Janssen, Zoltán Szekanecz: None declared, Edward C. Keystone Speakers bureau: Abbott, Amgen, AstraZeneca, Biotest, Bristol-Myers Squibb, Eli Lilly, Genentech, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Consultant of: Abbott, Amgen, AstraZeneca, Biotest, Bristol-Myers Squibb, Eli Lilly, Genentech, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: Abbott, Amgen, AstraZeneca, Biotest, Bristol-Myers Squibb, Eli Lilly, Genentech, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Andrea Rubbert-Roth Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and Sanofi, Stephen Hall Grant/research support from: Pfizer, Ricardo Xavier: None declared, Joaquim Polido-Pereira: None declared, In-Ho Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Naomi Martin Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Samuel Anyanwu Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB.

Aim. Examine the efficacy of once-weekly subcutaneous tocilizumab (SC-TCZ) on joint damage at 24 weeks based on radiography of the hands and feet and magnetic resonance imaging (MRI) of the hand in subjects with moderate to severe rheumatoid arthritis (RA). Methods. In this Australian open-label, multicentre, prospective, single-arm study, subjects received 162 mg SC-TCZ weekly. Primary endpoint was change in radiographic Genant-modified Total Sharp Score (TSS) between baseline and Week 24. Secondary endpoints included change from baseline to Week 24 in RA MRI scoring (RAMRIS) of erosions, synovitis, and osteitis and Cartilage Loss Score (CARLOS) in the dominant hand and disease activity score 28 (DAS28). Results. 52 subjects were enrolled (80% female, mean (SD) age 57 (12) years). Radiography showed mild but not significant progression of joint damage (mean (SD) change in TSS 0.46 (1.29)). Synovitis reduced significantly on MRI; however, osteitis, erosion, and cartilage loss did not change significantly. DAS28 improved significantly by Week 24; 78% of subjects achieved DAS28 remission. SC-TCZ was generally well tolerated. Conclusion. Synovitis and DAS28 decreased significantly; however, no significant change in osteitis or joint damage was observed at Week 24. Trial registration. This trial is registered with Clinicaltrials.gov registration number NCT01951170 (ML28703).

Roche. F. Hoffmann-La Roche, Ltd (Roche) Objectives This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD).Methods Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162mg weekly+placebo-IV every 4weeks or tocilizumab-IV 8mg/kg every 4weeks+placebo-SC weekly in combination with traditional DMARD. the primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM). Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments.Results At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups -4.0%, 95% CI -9.2 to 1.2); the 12% NIM was met. ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups. the safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection. Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group. No anaphylaxis was reported over the 24weeks.Conclusions Tocilizumab-SC 162mg weekly demonstrated comparable efficacy to tocilizumab-IV 8mg/kg. the safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration. Charite, D-10117 Berlin, Germany Free Univ Berlin, Berlin, Germany Humboldt Univ, D-10099 Berlin, Germany Klinikum Univ Koln, Cologne, Germany Ctr Hosp Univ Toulouse, Toulouse, France Cabrini Med Ctr, Malvern, Australia Poznan Univ Med Sci, J Strus Poznan Municipal Hosp, Poznan, Poland Universidade Federal de São Paulo, São Paulo, Brazil Arthrit & Diabet Clin Inc, Monroe, LA USA Rheumatol Associates PA, Charleston, SC USA East Penn Rheumatol Associates PC, Bethlehem, PA USA Hoffmann La Roche Inc, Nutley, NJ 07110 USA Roche Prod Ltd, Welwyn Garden City AL7 3AY, Herts, England Genentech Inc, San Francisco, CA 94080 USA Org Med Invest, Buenos Aires, DF, Argentina Universidade Federal de São Paulo, EPM, São Paulo, Brazil Web of Science

Systemic lupus erythematosus is a heterogeneous autoimmune disease that is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of B-lymphocyte stimulator (BLyS). The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) was assessed in patients with active systemic lupus erythematosus.Patients (aged ≥18 years) who were seropositive with scores of at least 6 on the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) were enrolled in a multicentre phase 3 study, which was done in Latin America, Asia-Pacific, and eastern Europe. Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, with standard of care. Patients, investigators, study coordinators, and sponsors were masked to treatment assignment. Primary efficacy endpoint was improvement in the Systemic Lupus Erythematosus Responder Index (SRI) at week 52 (reduction ≥4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [0·3 increase] in Physician's Global Assessment [PGA] score) versus baseline. Method of analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00424476.867 patients were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288). 865 were treated and analysed in the belimumab (1 mg/kg, n=288; 10 mg/kg, n=290) and placebo groups (n=287). Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51%], odds ratio 1·55 [95% CI 1·10-2·19]; p=0·0129) and 10 mg/kg (167 [58%], 1·83 [1·30-2·59]; p=0·0006) than with placebo (125 [44%]) at week 52. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53%], 1·51 [1·07-2·14]; p=0·0189) and 10 mg/kg (169 [58%], 1·71 [1·21-2·41]; p=0·0024) than with placebo (132 [46%]). More patients given belimumab 1 mg/kg (226 [78%], 1·38 [0·93-2·04]; p=0·1064) and 10 mg/kg (236 [81%], 1·62 [1·09-2·42]; p=0·0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73%]). No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79%], 1·68 [1·15-2·47]; p=0·0078) and 10 mg/kg (231 [80%], 1·74 [1·18-2·55]; p=0·0048) than with placebo (199 [69%]). Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (1%), two (1%), and no patients, respectively. No malignant diseases were reported.Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease.Human Genome Sciences and GlaxoSmithKline.

This research explores the relationship between rheumatoid arthritis (RA) severity measures, clinical characteristics, and patient preference-based health-related quality of life (ie, utility) in Australian RA patients. A secondary objective was to investigate the relationship between a range of disease severity measures, clinical characteristics, and the cost of RA-related resource use.This was a cross-sectional, multicenter study of consecutive patients with RA agedor =18 years attending routine clinical appointments. Patients completed a questionnaire comprising general demographic, resource use, and disease-specific questions; the RA-specific Health Assessment Questionnaire (HAQ); and 2 multiattribute preference-based quality-of-life (utility) instruments, the Health Utilities Index Mark 3 (HUI3) and the EuroQol 5 Dimensions (EQ-5D). A second questionnaire was completed by the patient's rheumatologist, with questions on key clinical data pertinent to RA, including the number and location of tender joints and swollen joints, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) concentration, current and previous treatments, and details of important comorbid conditions. Data on RA-specific resource use were also collected, including health-professional visits (eg, general practitioner, specialist, nurse, occupational therapist, paid caregivers), hospital admissions, surgery, and RA-associated home modifications. Spearman nonparametric correlation, simple linear, multiple, and stepwise regression analyses were used to explore the relationship between utility scores (HUI3 and EQ-5D) and variables including HAQ, RA-related resource use, and key demographic, physical, and biochemical measures.A total of 170 patients were recruited from 4 centers in Australia. Consistent with the epidemiology of RA, the ratio of women to men was approximately 3:1 (126 vs 44, respectively). Male and female patients were of similar age (mean [SD], 59.2 [12.9] and 58.9 [12.2] years, respectively). Time since diagnosis of RA was significantly shorter for men than for women (mean difference, -4.52 years; 95% CI, -8.65 to -0.38; P = 0.03). Of all the disease severity measures and clinical characteristics investigated, patients' HAQ scores predicted their utility most closely (for HUI3, R(2) = 0.626, P0.001; for EQ-5D, R(2) = 0.403, P0.001). The Disease Activity Score 28 severity index provided the next best relationship with a patient's utility; however, its explanatory power was poor (for HUI3, R(2) = 0.085, P0.001; for EQ-5D, R(2) = 0.042, P = 0.008). ESR, CRP, and, RA-affected joint counts had negligible explanatory power for patient utility. In analyses of the relationship between a range of key variables and the direct costs associated with RA, the HAQ score explained 22% of the variability in log costs (P0.001).This study found that of all the disease severity measures and clinical characteristics investigated, patients' HAQ scores predicted their utility most closely.

ObjectiveTo evaluate the efficacy and safety of golimumab to 52 weeks in patients with active rheumatoid arthritis despite methotrexate.MethodsPatients were randomly assigned to receive placebo plus methotrexate (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus methotrexate (group 3) and golimumab 100 mg plus methotrexate (group 4). At week 16, patients in groups 1, 2 and 3 who had less than 20% improvement in tender and swollen joints entered early escape. At week 24, patients in group 1 who had not entered early escape crossed over to 50 mg golimumab plus methotrexate.ResultsAt week 16, 31%, 27% and 17% of patients in groups 1, 2 and 3, respectively, entered early escape. At week 52, 44%, 45%, 64% and 58% of patients in groups 1, 2, 3 and 4, respectively, achieved 20% improvement in the American College of Rheumatology criteria; and 34%, 31%, 42% and 53%, respectively, achieved low disease activity (≤3.2) according to the 28-joint disease activity score. Patients in group 4 appeared to have an increased risk of serious adverse events and serious infections.ConclusionThe results of various outcome measures showed that the response rates achieved by patients receiving golimumab to 24 weeks were sustained to 52 weeks. The safety profile appeared to be consistent with the known safety profile of tumour necrosis factor inhibitors.

Summary Background Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis. The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis (COMET) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept. Methods 542 outpatients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3–24 months were randomly assigned to receive either methotrexate alone titrated up from 7·5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate (same titration) plus etanercept 50 mg a week. Coprimary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints (DAS28) and radiographic non-progression measured with modified total Sharp score. Treatment was allocated with a computerised randomisation and enrolment system, which masked both participants and carers. Analysis was done by modified intention to treat with last observation carried forward for missing data. This study is registered with ClinicalTrials.gov, number NCT00195494). Findings 274 participants were randomly assigned to receive combined treatment and 268 methotrexate alone. 132 of 265 (50%, 95% CI 44–56%) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 (28%, 23–33%) taking methotrexate alone (effect difference 22·05%, 95%CI 13·96–30·15%, p 5·1). 196 of 246 (80%, 75–85%) and 135 of 230 (59%, 53–65%), respectively, achieved radiographic non-progression (20·98%, 12·97–29·09%, p Interpretation Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate. Funding Wyeth Research.

Objective. To assess the efficacy, safety, and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis (RA) despite treatment with methotrexate (MTX). Methods. Patients were randomly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48. Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16. The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least I of the individual dose groups were compared with placebo. Results. The primary end point was attained. Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37% of patients in the placebo plus MTX group (P = 0.010). In addition, 79% of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response (P < 0.001 versus placebo). Through week 20 (after which patients receiving placebo were switched to active infliximab therapy), serious adverse events were reported in 9% of patients in the combined golimumab groups and in 6% of patients in the placebo group. Conclusion. Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX.

Roche F. Hoffmann-La Roche, Ltd. Objectives To evaluate the long-term efficacy and safety of subcutaneous (SC) tocilizumab (TCZ) versus intravenous (IV) TCZ, including switching formulations, in patients with rheumatoid arthritis (RA) and inadequate response to disease-modifying antirheumatic drugs (DMARDs). Methods Patients (n=1262) were randomised 1: 1 to receive TCZ-SC 162 mg weekly (qw)+placebo-IV every four weeks (q4w) or TCZ-IV 8 mg/kg q4w+placebo-SC qw in combination with DMARD(s). After a 24-week double-blind period, patients receiving TCZ-SC were re-randomised 11: 1 to TCZ-SC (n=521) or TCZ-IV (TCZ-SCIV, n=48), and patients receiving TCZ-IV were re-randomised 2: 1 to TCZ-IV (n=372) or TCZ-SC (TCZ-IV-SC n=186). Maintenance of clinical responses and safety through week 97 were assessed. Results The proportions of patients who achieved American College of Rheumatology (ACR) 20/50/70 responses, Disease Activity Score in 28 joints remission and improvement from baseline in Health Assessment Questionnaire Disability Index >= 0.3 were sustained through week 97 and comparable across arms. TCZ-SC had a comparable safety profile to TCZ-IV through week 97, except that injection site reactions (ISRs) were more common with TCZ-SC. Safety profiles in patients who switched were similar to those in patients who received continuous TCZ-SC or TCZ-IV treatment. The proportion of patients who developed anti-TCZ antibodies remained low across treatment arms. No association between anti-TCZ antibody development and clinical response or adverse events was observed. Conclusions The long-term efficacy and safety of TCZ-SC was maintained and comparable to that of TCZ-IV, except for ISRs. Profiles in patients who switched formulations were comparable to those in patients who received TCZ-IV or TCZ-SC. TCZ-SC provides additional treatment options for patients with RA. Free Univ Berlin, Berlin, Germany Humboldt Univ, D-10099 Berlin, Germany Klinikum Univ Koln, Cologne, Germany Ctr Hosp Univ Toulouse, Toulouse, France Cabrini Med Ctr, Malvern, Vic, Australia Poznan Med Univ, Poznan, Poland Univ Fed Sao Paulo, Sao Paulo, Brazil Arthrit & Diabet Clin Inc, Monroe, LA USA Rheumatol Associates South Carolina, Charleston, SC USA East Penn Rheumatol Associates, Bethlehem, PA USA Genentech Inc, San Francisco, CA 94080 USA Roche Prod Ltd, Welwyn Garden City AL7 3AY, Herts, England Org Med Invest, Buenos Aires, DF, Argentina Universidade Federal de São Paulo, São Paulo, Brazil Web of Science

Apoptosis is a mode of cell death currently thought to occur in the absence of inflammation. In contrast, inflammation follows unscheduled events such as acute tissue injury which results in necrosis, not apoptosis. We examined the relevance of this paradigm in three distinct models of acute lung injury; hyperoxia, oleic acid, and bacterial pneumonia. In every case, it was found that apoptosis is actually a prominent component of the acute and inflammatory phase of injury. Moreover, using strains of mice that are differentially sensitive to hyperoxic lung injury we observed that the percent of apoptotic cells was well correlated with the severity of lung injury. These observations suggest that apoptosis may be one of the biological consequences during acute injury and the failure to remove these apoptotic cells may also contribute to the inflammatory response.

BACKGROUND Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. OBJECTIVE To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs. DESIGN 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544). SETTING 114 centers in 19 countries. PATIENTS 792 patients with active RA despite nonbiologic DMARD therapy. INTERVENTION Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily. MEASUREMENTS Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. RESULTS Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups. LIMITATIONS Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited. CONCLUSION Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate. PRIMARY FUNDING SOURCE Pfizer.

Objective.To assess the longterm efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy.Methods.We randomized 444 RA patients with inadequate response to MTX (3:3:2:2) to placebo + MTX (Group 1), golimumab 100 mg + placebo (Group 2), golimumab 50 mg + MTX (Group 3), or golimumab 100 mg + MTX (Group 4). Subcutaneous golimumab/placebo was injected every 4 weeks. Patients could escape early (Group 1 added golimumab 50 mg, Group 2 added MTX, Group 3 increased golimumab to 100 mg, Group 4 continued 100 mg) based on Week 16 swollen and tender joint counts. From Week 24, Group 1 patients received golimumab 50 mg + MTX. After the Week 52 database lock, patients in the longterm extension received golimumab 50–100 mg ± MTX. Coprimary endpoints [Week 14 American College of Rheumatology (ACR)20, Week 24 Health Assessment Questionnaire Disability Index (HAQ-DI)] and Week 52 findings have been published; 2-year findings (observed data by randomized group, no imputation) are presented.Results.Of 444 randomized patients, 392 continued from Week 52 (Group 1: n = 116, Group 2: n = 116, Group 3: n = 84, Group 4: n = 76). Clinical improvement was maintained through Week 104; ∼75% and 72% of patients randomized to golimumab 50 mg + MTX and 100 mg + MTX achieved ACR20 response, respectively. The majority [88% (105/120)] of golimumab + MTX–treated patients with Week 24 HAQ-DI improvement ≥ 0.25 maintained improved physical function through Week 104. Group 1 patients with delayed golimumab treatment exhibited more Week 104 radiographic progression (mean change score = 1.15) than golimumab + MTX-randomized patients (0.52). Incidences of serious infections were 2.24, 4.77, 5.78/100 patient-years of followup for golimumab 50 mg + MTX, 100 mg + placebo, and 100 mg + MTX, respectively.Conclusion.Clinical improvement was maintained and no new safety signals were identified with 2 years of golimumab + MTX. Golimumab efficacy and safety, including serious infections, will continue to be monitored through 5 years (Clinical Trial No. NCT00264550).

Background Clinical efficacy of subcutaneous tocilizumab (SC-TCZ) has been demonstrated in rheumatoid arthritis (RA); however the effect of SC-TCZ on joint damage has not yet been assessed. AC-CUTE (NCT01951170) aimed to evaluate the effects of weekly SC-TCZ on structural change in patients (pts) with moderate-severe active RA, who were inadequate responders to MTX/MTX-intolerant or inadequate responders to a single anti-TNF. Objectives To assess radiographic and MRI progression at week 24, in pts receiving SC-TCZ as monotherapy or in combination with MTX and/or conventional (c) DMARDs. Methods An open-label, multi-centre, prospective, single-arm study. Pts received TCZ 162mg weekly, single fixed dose SC injection, monotherapy or in combination with MTX or other cDMARDs. Primary endpoint was absolute change in radiographic Genant-modified Sharp Score (mTSS) between screening and week-24. Secondary endpoints were absolute change from baseline in RAMRIS of MRI erosions, synovitis and osteitis, and MRI cartilage loss (CARLOS). Efficacy parameters included change from baseline (initiation of SC-TCZ) in mTSS, DAS28, CDAI, SDAI and ACR20/50/70. The full analysis set population included pts who received at least 1 dose SC-TCZ, and was used for reporting safety, tolerability and efficacy. Subgroup analyses were split into SC-TCZ monotherapy [SC-TCZM: SC-TCZ monotherapy or SC-TCZ+cDMARDs other than MTX] and SC-TCZ in combination [SC-TCZC: SC-TCZ+cDMARDs including all MTX regimens]. Results 52 pts enrolled from 10 Australian sites; majority females (79%), median age 59 yrs (min 28, max 79) and 5 yrs (min 0, max 31) median duration of RA. Pts in SC-TCZM had longer disease duration at baseline and higher mTSS score. 29 pts completed 24 weeks of treatment. Mean change from baseline for erosion/JSN/mTSS was 0.162/0.485/0.647 in SC-TCZM and 0.124/0.238/0.362 in SC-TCZC respectively; changes relative to baseline and between subgroups were not significant (p>0.05). Mean changes from baseline in MRI erosion/cartilage loss/synovitis/osteitis were 0.794/0.0882/-1.56/-2.88 for SC-TCZM and 0.955/0.1439/-1.68/-3.77 for SC-TCZC. Change from baseline for each MRI measure within SC-TCZC was significant (p 0.1). At 24 weeks, decrease in DAS28 from baseline was significant for both subgroups (p=0.004 for SC-TCZC; p Conclusions There was no significant radiographic progression during the study period across groups. Mean changes in MRI variables were not significant in SC-TZM. MRI changes in SC-TCZC were significant for joint damage progression, as well as regression of synovitis and osteitis. Acknowledgement Sponsored by Roche Products, Pty. Ltd. Medical writing provided by Joseline Ojaimi from Roche. Disclosure of Interest P. Bird: None declared, C. Peterfy Consultant for: Roche Products, Pty. Ltd, J. DiCarlo Consultant for: Roche Products, Pty. Ltd, F. Joshua: None declared, S. Hall: None declared, H. Griffiths: None declared, P. Youssef: None declared, R. Barrett Employee of: Roche Products, Pty. Ltd, P. Button Employee of: Roche Products, Pty. Ltd

Background The treatment of Rheumatoid arthritis (RA) in Australia is consistent with the current international guidelines of starting a biologic (b) DMARD in combination with methotrexate (MTX) where possible and/or other synthetic DMARDs with or without glucocorticoids (GCs). There is limited data available on the effects of various bDMARDs on oral GCs consumption in a real world data setting and in the same patient population. Objectives The objective of the study was to investigate the usage of concomitant GCs with bDMARDs for the treatment of RA patients over time. Methods Concessional (government subsidised) RA patients ≥18 years of age for whom bDMARDs were first dispensed for their RA (between 01August 2010 and 31July 2013), and who were in the Australian Medicare 10% sample database provided by the Department of Health and Aging through an Australian healthcare consulting company (PROSPECTION) were followed for a period of 2 years (until 31 July 2015). bDMARDs included: abatacept (IV and SC), adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, and tocilizumab. Data were analysed using descriptive statistics for continuous variables and frequency counts for categorical variables. Individual anti-TNFs were equivalent in all analyses and therefore were combined for simplicity. Results Data from 269 patients were analysed. Of the patients who received oral GCs at some point during the study period (86%; n=230), 49% were ≥65 years old and 51% were 18–64 years old. The majority (81%) were females. For all patients, median dose of oral GCs was 4.1 (min 0, max 21) mg/day at one year prior to initiation of a bDMARD, 2.9 (min 0, max 22.2) mg/day and 2.0 (min 0, max 17.3) mg/day at 1 and 2 years, respectively, post-bDMARDs initiation. Daily GCs doses across the analysis time points and by drug group are presented in Table 1. Daily dose changes at 1–2 years post initiation of bDMARDs from 1 year before initiation of bDMARDs were statistically significant for all bDMARDs (p Conclusions In the Australian setting, the majority of RA patients who were taking oral GCs had reductions in their daily GCs doses after initiation of bDMARDs; which continued for up to 2 years post treatment initiation. Acknowledgement The study was sponsored by Roche Products Pty. Limited. Medical writing was provided by Dr Joseline Ojaimi from Roche. Disclosure of Interest G. Jones: None declared, S. Hall: None declared, G. Littlejohn: None declared, E. Chung Consultant for: Roche Products, Pty. Ltd, R. Barrett Employee of: Roche Products, Pty. Ltd, P. Button Employee of: Roche Products, Pty. Ltd

(Orgeig and Daniels) This surfactant symposium reflects the integrative and multidisciplinary aims of the 1st ICRB, by encompassing in vitro and in vivo research, studies of vertebrates and invertebrates, and research across multiple disciplines. We explore the physical and structural challenges that face gas exchange surfaces in vertebrates and insects, by focusing on the role of the surfactant system. Pulmonary surfactant is a complex mixture of lipids and proteins that lines the air-liquid interface of the lungs of all air-breathing vertebrates, where it functions to vary surface tension with changing lung volume. We begin with a discussion of the extraordinary conservation of the blood-gas barrier among vertebrate respiratory organs, which has evolved to be extremely thin, thereby maximizing gas exchange, but simultaneously strong enough to withstand significant distension forces. The principal components of pulmonary surfactant are highly conserved, with a mixed phospholipid and neutral lipid interfacial film that is established, maintained and dynamically regulated by surfactant proteins (SP). A wide variation in the concentrations of individual components exists, however, and highlights lipidomic as well as proteomic adaptations to different physiological needs. As SP-B deficiency in mammals is lethal, oxidative stress to SP-B is detrimental to the biophysical function of pulmonary surfactant and SP-B is evolutionarily conserved across the vertebrates. It is likely that SP-B was essential for the evolutionary origin of pulmonary surfactant. We discuss three specific issues of the surfactant system to illustrate the diversity of function in animal respiratory structures. (1) Temperature: In vitro analyses of the behavior of different model surfactant films under dynamic conditions of surface tension and temperature suggest that, contrary to previous beliefs, the alveolar film may not have to be substantially enriched in the disaturated phospholipid, dipalmitoylphosphatidylcholine (DPPC), but that similar properties of rate of film formation can be achieved with more fluid films. Using an in vivo model of temperature change, a mammal that enters torpor, we show that film structure and function varies between surfactants isolated from torpid and active animals. (2) Spheres versus tubes: Surfactant is essential for lung stabilization in vertebrates, but its function is not restricted to the spherical alveolus. Instead, surfactant is also important in narrow tubular respiratory structures such as the terminal airways of mammals and the air capillaries of birds. (3). Insect tracheoles: We investigate the structure and function of the insect tracheal system and ask whether pulmonary surfactant also has a role in stabilizing these minute tubules. Our theoretical analysis suggests that a surfactant system may be required, in order to cope with surface tension during processes, such as molting, when the tracheae collapse and fill with water. Hence, despite observations by Wigglesworth in the 1930s of fluid-filled tracheoles, the challenge persists into the 21st century to determine whether this fluid is associated with a pulmonary-type surfactant system. Finally, we summarize the current status of the field and provide ideas for future research.

Background Current guidelines for rheumatoid arthritis (RA) recommend starting a biologic DMARD in combination with methotrexate (MTX) in patients responding insufficiently to MTX and/or other synthetic disease modifying anti-rheumatic drugs (DMARDs) with or without glucocorticoids. There is limited data on drug survival studying all modes of action in the same population. Objectives The primary objective was to describe the persistence on biologic (b) DMARDS in the Australian landscape. The secondary objectives were to investigate the influence of MTX and other DMARD concomitant medications, effect of patient age at initiation and bDMARD treatment line on biologic persistence. Methods RA patients aged ≥18 for whom biologics were dispensed for their RA and who were in the Australian Medicare 10% sample database (dating from 01 August 2010 to 31 June 2014) provided by the Department of Health and Aging through an Australian healthcare consulting company (PROSPECTION) were included in the study. The following bDMARDS were included abatacept (ABA), adalimumab, certolizumab pegol, etanercept, golimumab, infliximab (INF) and tocilizumab (TCZ). The duration of treatment was determined for each treatment regimen. Data were analysed using descriptive statistics for continuous variables and frequency counts for categorical variables. Time-to endpoints was summarised using Kaplan-Meier (K-M) methodology. Individual sub-cutaneous (SC) anti-TNFs were equivalent in all analyses and therefore were combined for simplicity. Results Data from 1230 patients were included in the analysis; 27% were ≥65 years old and 73% were between 18-64 years old. The majority (73%) were females. For all patients, the percentage (based on K-M estimates) who continued on treatment at 6 months (mo) after commencement was 84% for TCZ, 75% for ABA, 69% for SC anti-TNFs and 40% for INF. Median time to stopping treatment was 39 mo (95% CI:29-ND) for TCZ, 32 mo (95% CI:19-ND) for ABA; 21 mo (95% Cl:17-26) for SC anti-TNF, and 3 mo (95% CI:1-12) for INF. Longer median treatment persistence was observed for concomitant SC anti-TNFs and ABA with MTX or other DMARDs than for monotherapy (but not TCZ; Table 1). Age was not associated with treatment persistence. Significant differences were observed for treatment line and persistence (Table 2). Conclusions As first line therapy, ABA and possibly TCZ (p=0.08) have superior persistence compared to SC anti-TNFs. For second line, TCZ was superior to all other options and, for third line, none were different but this was hampered by small numbers. MTX and other DMARDs improve persistence for ABA and SC anti-TNF but not TCZ. These real world data help inform clinicians about choice of therapy at initiation and the use of concomitant DMARDs. Acknowledgements The study was sponsored by Roche Products, Pty, Limited. Medical writing was provided by Dr Joseline Ojaimi from Roche. Disclosure of Interest G. Jones: None declared, P. Bird: None declared, S. Hall: None declared, G. Littlejohn: None declared, K. Tymms: None declared, P. Youssef: None declared, E. Chung Consultant for: Roche Products Pty Limited, C. Bennett Employee of: Roche Products Pty Limited, P. Button Employee of: Roche Products Pty Limited

The major component of the recoil forces that tend to deflate the lungs is the surface tension of a thin liquid layer that lines the alveoli. This surface tension is well below the value for a clean air/water interface, indicating the presence of a surfactant. The surface tensions in situ specify that the surfactant films must have certain characteristics. Following large expansions of the air/water interface during deep inhalations, the surfactant must adsorb rapidly to form the interfacial film. When compressed by the shrinking surface area during exhalation, the films must be sufficiently rigid to resist the tendency to collapse from the interface. Materials washed from the lungs show that pulmonary surfactant is a mixture containing mostly lipids with some proteins that is synthesized and secreted by the type II pneumocyte. The disorder in which an abnormality of pulmonary surfactant most clearly plays a role is the respiratory distress syndrome of premature babies, although altered surfactant function may also contribute to the acute respiratory distress syndrome that occurs in patients of all ages.

Background The efficacy and safety profile of intravenous (IV) tocilizumab (TCZ) has been well established in patients (pts) with rheumatoid arthritis (RA). The aim of a subcutaneous (SC) TCZ dosing regimen is to provide the convenience of patient home use and self-administration. In the BREVACTA study, the primary endpoint was met by demonstrating superiority of TCZ SC 162 mg q2w over placebo for ACR20 response at 24 weeks (ACR 2012). Objectives The objective of SUMMACTA study was to compare the efficacy and safety of TCZ SC and TCZ IV regimens in pts with adult RA who had an inadequate response to DMARDs (up to 20% may have failed one or more anti-TNF agents). Methods SUMMACTA is a 2-year, Phase 3 trial, which is a randomized, active controlled, parallel group study that includes a 24-week double-blind (DB) period, followed by a 72-week open-label phase. During the DB period, pts received TCZ SC 162 mg qw + placebo IV q4w or TCZ IV 8mg/kg q4w + placebo SC qw, in combination with traditional DMARDs. The primary endpoint was the proportion of patients achieving an ACR20 response at Week 24. The hypothesis of non-inferiority of TCZ SC with respect to TCZ IV regarding ACR20 response was tested by means of the 95% confidence interval (CI) and with a 12% non-inferiority margin (NIM). Additional clinical efficacy, immunogenicity and safety assessments were evaluated as secondary outcomes. Pts were stratified at baseline by body weight and region. Results A total of 1262 pts were enrolled globally. All patients’ baseline characteristics were well balanced between TCZ SC and TCZ IV groups, including age, RA disease duration and DAS 28-ESR. At Week 24, 69.4% (95% CI: 65.5, 73.2) of TCZ SC-treated pts achieved an ACR20 response versus 73.4% (95% CI: 69.6, 77.1) of TCZ IV-treated pts. The weighted difference between groups was -4.0% [95% CI: -9.2, 1.2]) and a 12% NIM was met. ACR50/70 responses, disease activity and physical function improvements were also comparable between the TCZ SC and TCZ IV groups. Up to Week 24, the proportions of pts with at least one adverse event (AE) or serious AE were 76.2% and 4.6%, respectively, in the TCZ SC group compared with 77.0% and 5.2%, respectively, in the TCZ IV group. The most common AE in both groups was infection. Injection site reactions occurred more frequently in the TCZSC group than the TCZ IV group (10.1% vs 2.4%, respectively); but none required dose interruption or study withdrawal. No anaphylaxis was reported over the 24-week period. Conclusions TCZ SC 162mg qw demonstrated efficacy and safety profile comparable to TCZ IV 8mg/kg q4w. The TCZ-SC formulation could provide an additional, more convenient administration option and opportunity for home injection for patients with RA. Disclosure of Interest G. Burmester Grant/research support from: Roche, Abbott, Pfizer, UCB, BMS, MSD, Consultant for: Roche, Chugai, Pfizer, UBC, BMS, Speakers bureau: Roche, Pfizer, MSD, BMS, Abbott, A. Rubbert-Roth Grant/research support from: Roche, Pfizer, Consultant for: Roche, Chugai, Pfizer, MSD, Abbott, UCB, Speakers bureau: Roche, UCB, A. Cantagrel Grant/research support from: UCB, Pfizer, Consultant for: BMS, Chugai, Roche, UCB, Abbott, Pfizer, S. Hall: None Declared, P. Leszczynski Consultant for: Roche, D. Feldman: None Declared, M. Rangaraj Grant/research support from: Roche, G. Roane: None Declared, C. Ludivico Grant/research support from: Roche, BMS, Pfizer, Human Genome Science, Lilly, Sanofi-Aventis, Speakers bureau: BMS, E. Mysler Grant/research support from: Roche, Consultant for: Roche, Speakers bureau: Roche, L. Rowell Employee of: Roche, I. Vranic Employee of: Roche

Background Clinical trial data suggest that the duration of rheumatoid arthritis (RA) may influence response, but most trials have been conducted in patients with severe disease. Less attention has been paid to patients with moderately active RA, who represent a larger group of patients treated in rheumatology clinics. Objectives The objective of this post hoc analysis from the PRESERVE trial was to determine the relationship between RA duration and the efficacy of combination ETN–MTX therapy in patients with moderately active RA. Methods Enrolled subjects had DAS28 >3.2 and ≤5.1 despite stable oral MTX doses and received open-label ETN 50 mg QW plus MTX for 36 wks. Subjects (n=832) were stratified into disease duration subgroups (≤2 y vs >2 y) and analyzed in a one-way analysis of variance for demographic/baseline (BL) disease variables and for BL/Wk 36 mean weekly MTX doses, and in regression models for Wk 36 annualized radiographic and clinical treatment responses. Results Significant differences ( P 2 y were observed for: age (46.5 vs 49.1 y, mean); racial distribution (Asian, 16.8% vs 10.9%); RF+ (62.7% vs 76.7%); and aCCP+ (67.4% vs 81.7%). Disease duration was not significantly associated with mean weekly dosage of MTX at BL or Wk 36. No significant differences were observed between subgroups in the proportions of subjects achieving ACR20/50/70, DAS28 or SDAI low disease activity or remission, normal HAQ (≤0.5), or normal CRP (≤ULN) at Wk 36. Subjects in the >2 y subgroup were significantly more likely to achieve radiographic non-progression (Δ in mTSS ≤0.0; OR 1.76, 95% CI 1.11-2.77), but the estimated mean (SD) BL annual rate of progression was significantly lower in this group (6.0 [6.6] vs 16.6 [39.2], P Conclusions ETN-MTX therapy was effective in improving RA signs and symptoms in subjects with moderately active RA and an inadequate response to MTX, regardless of disease duration. Subjects with longer disease duration were significantly more likely to achieve non-progression and experienced a lower mean rate of progression. Among subjects with shorter duration, a lower proportion were RF+ and aCCP+; further analyses are planned to examine the distribution of these markers. Disclosure of Interest S. Hall: None Declared, A. Szumski Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., A. Koenig Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., T. Jones Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.

The hydrophobic surfactant proteins, SP-B and SP-C (SPs), promote rapid adsorption of phospholipids to an air-water interface by a mechanism that remains unclear. To understand the structural changes that lead to faster adsorption, we measured small-angle X-ray diffraction from dipalmitoylphosphatidylcholine (DPPC) bilayers containing varying concentration of SPs on solid supports. Swelling at different hydration allowed interpretation of the diffracted intensities and construction of the electron density profile. With increasing concentrations of protein (0 - 10 wt/wt %), the d-spacing and bilayer thickness increased. This change may reflect stretching of the hydrophobic region of the bilayer caused by the presence of the protein. Larger amounts of protein also flattened the electron density profiles, reducing the difference between minimum and maximum densities. A disordering effect of the proteins should cause greater thermal fluctuations of the bilayer, which would explain both the flattened density profile and the observed loss of higher order Bragg peaks.Figure 1: Electron density profiles of DPPC samples containing varying amount of SPs.View Large Image | View Hi-Res Image | Download PowerPoint SlideAcknowledgements: Stanford Synchrotron Radiation Lightsource (SSRL); NIH.

Rabbits treated with intravenous free fatty acid suffer an acute lung injury. Material obtained from these lungs by bronchoalveolar lavage (BAL) has dramatically impaired ability to lower surface tension in vitro despite normal levels of surfactant phospholipids. Although large quantities of surface-active inhibitors are present in BAL, their effects are not sufficient to explain the magnitude of surfactant inactivation. This study determines if alterations in the surfactant aggregates can explain the loss of surfactant function in fatty acid lung injury. In injured animals, the larger, most active surfactant particles recovered by centrifugal pelleting were found to be decreased in amount. The remaining large particles had reduced surface activity compared with control aggregates. In addition, large particles in injured animals had a higher density than control animals on sucrose gradients following equilibrium centrifugation. Interaction with serum components present in the injured BAL could explain these higher densities. The ability of the injured BAL to lower surface tension was improved by supplementation with normal levels of particles from injured lungs. Supplementation of injured BAL with control large aggregates improved activity further and restored the ability to lower surface tension to1 mN/m. Therefore both the decreased amount and activity of large surfactant aggregates in injured animals contributed significantly to the observed inactivation of surfactant. Diminished surfactant function from alteration in surfactant aggregates is a mechanism common to other forms of acute lung injury, and the design of therapies with exogenous surfactants in injured lungs will need to consider strategies that restore surfactant function towards normal.

The biophysical properties and physiologic effects of a series of clinical exogenous pulmonary surfactants was compared to determine the importance of the hydrophobic apoproteins (SP-B and C) as constituents of these preparations. The three exogenous surfactants studied, calf lung surfactant extract (CLSE), Survanta (Surfactant-TA), and Exosurf, all contain dipalmitoyl phosphatidylcholine (DPPC) as their major constituent. CLSE and Survanta also contain 1 to 2% of SP-B,C but Exosurf has the additives hexadecanol and tyloxapol instead to enhance the activity of DPPC. In adsorption experiments, CLSE reached a final surface tension of 22 mN/m, and Survanta and Exosurf reached 28 and 38 mN/m, respectively. Addition of 1% by weight of an apoprotein isolate containing both SP-B and C to Exosurf slightly improved its adsorption. In oscillating bubble studies, CLSE and Survanta decreased surface tension to low values of less than 1 and 2 mN/m, respectively, but Exosurf achieved a minimum value of only 29 mN/m. Addition of SP-B,C to Exosurf improved this minimum to 1 mN/m and approached the behavior of mixtures of synthetic DPPC with SP-B,C. In both adsorption and pulsating bubble experiments, the minimum surface tensions found for Exosurf were almost identical to those generated by tyloxapol alone. In studies of physiologic activity, 20 mg of CLSE or Survanta restored the pressure-volume mechanics of lavaged, surfactant-deficient excised rat lungs to 95 and 50%, respectively, of normal prelavage levels. Instillation of Exosurf (37.5 mg) produced a minimal improvement of only 10% compared to 70% for mixtures containing 1% SP-B,C with either Exosurf or DPPC.(ABSTRACT TRUNCATED AT 250 WORDS)

Biophysical activity and inhibition characteristics were studied for a series of synthetic surfactants composed of purified bovine lung surfactant proteins (SP)-B or -C combined with dipalmitoyl phosphatidylcholine (DPPC) and egg-phosphatidylglycerol (PG) in a weight ratio of 80:20:1 DPPC/PG/protein. Surfactant protein preparations included two isolates of SP-B, confirmed by amino terminal sequence analysis, three isolates of SP-C which were free of SP-B by ELISA and Western blot analysis, and two isolates containing both SP-B and -C. In oscillating bubble studies, mixtures of phospholipids with isolates containing pure SP-B or both SP-B and -C lowered surface tension to less than 1 mN/m within 2 min of pulsation at both 1.25 mg/ml and 2.5 mg/ml. Phospholipids combined with isolates of pure SP-C also had substantial activity, lowering surface tension to between 1 mN/m and 3 mN/m depending on the SP-C preparation used. The surface activity of synthetic phospholipid-apoprotein admixtures was decreased significantly by the plasma proteins albumin and fibrinogen, but with varying characteristics depending on the apoprotein preparation involved. At 1.25 mg/ml phospholipid, admixtures containing either isolate of SP-B were inhibited by 10 mg/ml of plasma proteins, as were those with one of the SP-C preparations. However, admixtures containing the two other pure SP-C preparations were not inhibited until 20-50 mg/ml of albumin or fibrinogen were present. The highest resistance to inhibition was shown by admixtures containing one of the apoprotein isolates having both SP-B and -C.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether acute fatty acid lung injury impairs pulmonary surfactant function, we studied anesthetized ventilated rabbits given oleic acid (55 mg/kg iv, n = 11) or an equivalent volume of saline (n = 8). Measurements of pulmonary mechanics indicated a decrease in dynamic compliance within 5 min of injury and a decrease in lung volume that was disproportionately large at low pressures, consistent with diminished surfactant activity in vivo. Bronchoalveolar lavage fluid obtained 1 h after injury had significantly increased erythrocytes and total leukocytes, largely polymorphonuclear cells. The phospholipid content and composition of the cell-free fraction had only minor changes from those of controls, but the protein content was increased 35-fold. Measurements of lavage surface activity in vitro showed an increase in average minimum surface tension from 1.3 +/- 0.4 (SE) dyn/cm in controls to 20.2 +/- 3.9 dyn/cm in injured animals. The alterations in static pressure-volume curves and decrease in lavage surface activity suggest a severe alteration of surfactant function in this form of lung injury that occurs despite the presence of normal amounts of surfactant phospholipids.

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Nineteen of 520 patients with biopsy-proven giant cell arteritis were found to have persistent seronegative, symmetric polyarthritis with a mean joint count of 20 (swollen plus tender). In 9 patients in the onset of polyarthritis occurred prior to the diagnosis of giant cell arteritis, 3 had simultaneous onset, and 7 developed polyarthritis within 3 years after the onset of giant cell arteritis. Ten of the 19 patients demonstrated radiographic features of joint space narrowing and/or erosions. In 1 patient in a synovial biopsy was performed, revealing marked multinucleated giant cell infiltration. A persistent seronegative polyarthritis, although uncommon in giant cell arteritis, may be its presenting symptom. Other symptoms of giant cell arteritis should be sought in patients who exhibit this feature, especially in those whose arthritis begins at age 50 or older.