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Background Abnormalities in lymphocyte surface markers and functions have been described in systemic sclerosis (SSc), but conflicting results abound, and these studies often examined patients with heterogeneous disease duration, severity, clinical phenotype, and concurrent immunosuppressive agents. We studied a clinically homogeneous group of early diffuse cutaneous SSc patients not exposed to immunosuppressive drugs who were enrolled in a clinical trial and compared their immune parameters to healthy control subjects. Methods Lymphocyte subsets were enumerated by multi-parameter flow cytometry of peripheral blood mononuclear cells at baseline visit. Production of the cytokines IL-4 and IL-17 was measured by intracellular flow cytometry following T cell activation. Results SSc patients had increased percentages of CD4+ T cells but lower percentages of CD8+ T cells versus controls. The CD28-negative population was expanded in SSc, in the CD4 subset. Striking expansion of CD319+ T cells was noted among the CD4+ cells, in which they were barely detectable in healthy subjects. Frequencies of IL-4 producing cells did not differ between SSc and controls, but expansion of IL-17 producing cells was observed in SSc. A higher proportion of CD319+ cells produced cytokines, compared to other CD4+ cells. Numbers of activated T cells, regulatory T cells, and B cells were similar in SSc and control groups. Circulating follicular helper but not peripheral helper T cells were slightly expanded in SSc. Conclusion In this carefully selected group of early diffuse cutaneous SSc patients, analysis of immune cell parameters has identified abnormalities that likely reflect disease pathogenesis and that are candidate biomarkers for sub-classification and targeted treatment. The CD4+CD319+ (SLAM-F7+) cells are cytotoxic and oligoclonal, were recently shown to be a dominant T cell population in perivascular lymphocytic infiltrates in SSc skin, actively secrete cytokines, and are emerging as a target for novel treatments of SSc.

Background To determine the effect of riociguat, an oral, selective soluble guanylate cyclase stimulator, on the net digital ulcer (DU) burden in systemic sclerosis (SSc). Methods Participants with SSc-related active or painful indeterminate DUs were recruited in a multicenter, double-blind, randomized, placebo-controlled, proof-of-concept trial. Eligible participants were required to have at least one visible, active ischemic DU or painful indeterminate DU at screening, located at or distal to the proximal interphalangeal joint and that developed or worsened within 8 weeks prior to screening. Participants were randomized 1:1 to placebo or riociguat in individualized doses (maximum of 2.5 mg three times daily) during an 8-week titration period, followed by an 8-week stable dosing period. This was followed by an optional 16-week open-label extension phase for participants with active DU/reoccurrence of DUs within 1 month of the end of the main treatment phase. The primary endpoint was the change from baseline to week 16 in net ulcer burden (NUB), analyzed using ANCOVA. Other endpoints included plasma biomarkers and proportion of participants with treatment-emergent adverse events (AEs). Results Seventeen participants (eight placebo, nine riociguat) were randomized at five centers. Six participants in each group transitioned to the open-label extension. Baseline characteristics were comparable between the treatment groups, except participants randomized to placebo were older and had longer disease duration (p

Background Abatacept (ABA) is a recombinant fusion protein including extracellular domain of human CTLA4 and hinge– CH2–CH3 of the Fc domain of human IgG. Objectives This phase 2 trial assessed the safety and efficacy of ABA 125 mg subcutaneous (SC) versus placebo SC given every week on skin fibrosis using the modified Rodnan skin score (mRSS) in diffuse cutaneous SSc (dcSSc; clinicaltrials.gov NCT02161406). Methods A 12-month, investigator-initiated, multicenter double-blind, randomized placebo-controlled trial was conducted between September 2014 and February 2018 at 27 US, Canadian and UK sites. Eligible subjects were randomized in a 1:1 ratio to either ABA or matching placebo, stratified by duration of dcSSc (≤18 vs >18 to ≤36 months). Key inclusion criteria included dcSSc with disease duration of ≤ 36 months (defined as first non−Raynaud phenomenon) and mRSS ≥ 10 and ≤ 35 units for disease duration of ≤ 18 months and mRSS ≥ 15 and ≤ 45 units with evidence of active disease for disease duration of >18-36 months. Escape therapy was allowed at 6 months for worsening SSc. Primary outcomes include safety and change in mRSS over 12 months (ΔmRSS). Secondary endpoints include ΔFVC%, ΔHAQ-DI, Δpatient and Δphysician global assessment, and ACR CRISS1 (composite measure in dcSSc). The primary endpoint of ΔmRSS was assessed using a linear mixed model (see Table) with primary end point data censored after initiation of escape therapy. Results 88 subjects were randomized (44/group) and formed the mITT group; 34 (77%) and 35 (80%) completed the 12-month double-blind treatment period in ABA and placebo groups, respectively. At baseline, the mean age was 49 years, 75% were female, mean disease duration was 1.59 years, 60% had disease duration ≤ 18 months, mRSS was 22.4, mean FVC% was 84.3%, and mean HAQ-DI was 1.0. Compliance with both drugs was >98%. ABA was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest (e.g., infections and malignancies) between treatments. There were 3 deaths during the treatment— 2 in ABA (both scleroderma renal crisis-days 11 and 46) and 1 in placebo (sudden cardiac arrest- day 310). The primary endpoint showed an adjusted mean improvement of mRSS of -6.24 in ABA vs. -4.49 in placebo, p= 0.28 (Table). The secondary outcome measures were statistically significant and clinically meaningful (HAQ-DI and physician global assessment) or showed numerical results favoring ABA (Table). A larger proportion of placebo subjects required escape immunosuppressive therapy vs. ABA (36% vs. 16%, p=0.03). Estimates are from a linear mixed model with treatment group, month (3, 6, and 12), treatment x month interaction, duration of dcSSc (≤18 vs >18 to ≤36 months), and baseline outcome measure as fixed effects and participant as a random effect (except for ACR CRISS). For ACR CRISS, treatment differences were assessed by the non-parametric Van Elteren test. Multiple imputation was used for ACR CRISS analysis. Conclusion In patients with early dcSSc, ABA was well tolerated, but ΔmRSS was not statistically significant. Secondary outcome measures showed evidence in favor of ABA, including greater requirement of escape therapy in the placebo group. mRSS showed large variability, despite recruiting an early dcSSc population. References [1] Khanna D, et al. Arthritis Rheumatol2016, 68:299-311 Acknowledgement Project was supported by NIH/NIAID Clinical ACE grant (5UM1AI110557-05) and an investigator-initiated grant by Bristol-Myers Squibb. Disclosure of Interests Dinesh Khanna Shareholder of: Eicos Sciences, Inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: Actelion Acceleron, Arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, Inc, Cathie Spino: None declared, Erica Bush: None declared, Sindhu Johnson: None declared, Lorinda Chung Grant/research support from: United Therapeutics, Consultant for: Reata, Bristol Meyers Squibb, Boehringer Ingelheim, Mitsubishi Tanabe, Eicos, Christopher Denton Grant/research support from: GlaxoSmithKline, Inventiva, CSF Behring, Consultant for: Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Bayer, Jerry Molitor Grant/research support from: Pfizer, Consultant for: Boehringer Ingelheim, Amgen, Viginia Steen Consultant for: CSL Behring, Corbus and Bayer, Paid instructor for: Advisory Board: CSL Behring, Roach, Bayer and Reata, Robert Lafyatis Grant/research support from: Kiniksa, Elpidera, Regeneron, PRISM biolab, Consultant for: Sanofi, Genentech, Formation, Biocon, Bristol Meyers Squibb, Merck, Robert Simms: None declared, Suzanne Kafaja: None declared, Tracy Frech: None declared, Vivian Hsu: None declared, Robin Domsic Consultant for: Eicos Sciences Inc/Civi Biopharma and Boehringer-Ingelheim., Janet Pope Consultant for: Eli Lilly and Company, Jessica Gordon Grant/research support from: Corbus Pharmaceuticals Cumberland Pharmaceuticals, Maureen Mayes Grant/research support from: Maureen Mayes is a clinical trial investigator for Boehringer-Ingelheim; Galapagos, Reata, Sanofi, Merck-Serono, Consultant for: Maureen Mayes is a member of scientific advisory boards for Galapagos NV (Pharma), Boehringer-Ingelheim, Mitsubishi-Tanabe, Astellas: Grant Review Board for Actelion., Speakers bureau: Maureen Mayes received personal fees for being a conference speaker on the use of autoantibodies in connective tissue diseases for Medtelligence, Elena Schiopu Grant/research support from: Bristol Meyers Squibb and Bayer, Amber Young: None declared, Nora Sandorfi: None declared, Jane Park: None declared, Faye Hant: None declared, Elana Bernstein Grant/research support from: I have an investigator-initiated research grant from the Pfizer ASPIRE Rheumatology Program., Consultant for: I am the medical monitor for SLS III, which is sponsored by Genentech, Soumya Chatterjee: None declared, Flavia Castelino Consultant for: Genentech, Boehringer, Ali Ajam Consultant for: Focus Point Global, Yannick Allanore Grant/research support from: Inventiva, F Hoffman La-Roche, Sanofi, BMS, Pfizer, Consultant for: Actelion, Bayer, BMS, Boehringer, Roche, Sanofi, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Pfizer, BMS, Chemomab, Sanipedia, Speakers bureau: Actelion, BMS; MSD, Janssen, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders, Ora Gewurz-Singer: None declared, David Fox Grant/research support from: Regeneron, Gilead, Seattle Genetics, Consultant for: Grant reviewer for Pfizer, Daniel Furst Grant/research support from: F. Hoffmann-La Roche, Genentech

ObjectiveT cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc).MethodsIn this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets.ResultsAmong 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively.ConclusionIn this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.

Objective In a pilot study, our group showed that an internet-based self-management program improves self-efficacy in systemic sclerosis (SSc). The objective of the current study was to compare an internet-based self-management program to a patient-focused educational book developed to assess measures of self-efficacy and other patient-reported outcomes in patients with SSc. Methods We conducted a 16-week randomized, controlled trial. Results Of the 267 participants who completed baseline questionnaires and were randomized to the intervention (internet: www.selfmanagescleroderma.com) or control (book) group, 123 participants (93%) in the internet group and 124 participants (94%) in the control group completed the 16-week randomized controlled trial (RCT). The mean ± SD age of all participants was 53.7 ± 11.7 years, 91% were women, and 79.4% had some college or a higher degree. The mean ± SD disease duration after diagnosis of SSc was 8.97 ± 8.50 years. There were no statistical differences between the 2 groups for the primary outcome measure (Patient-Reported Outcomes Measurement Information System Self-Efficacy for Managing Symptoms: mean change of 0.35 in the internet group versus 0.94 in the control group; P = 0.47) and secondary outcome measures, except the EuroQol 5-domain instrument visual analog scale score (P = 0.05). Internet group participants agreed that the self-management modules were of importance to them, the information was presented clearly, and the website was easy to use and at an appropriate reading level. Conclusion Our RCT showed that the internet-based self-management website was not statistically superior to an educational patient-focused book in improving self-efficacy and other measures. The participants were enthusiastic about the content and presentation of the self-management website.

An amendment to this paper has been published and can be accessed via the original article.

Date Presented 03/27/20 In the emerging field of telerehab, OTs can provide rehabilitation in novel ways, such as by using apps or other technologies. Adherence to home exercise is a critical part of sustaining therapeutic gains, but often home exercise is not completed and function may decline after discharge. We show how an app was used to track home exercises, as well as facilitators of and barriers to use. Such information will be important for practitioners when considering using apps and other technologies. Primary Author and Speaker: Susan Murphy Additional Authors and Speakers: Donnamarie Krause Contributing Authors: Erin Welsh, Angela Lyden, Mary Barber, Maya Sabbagh, Vivek Nagaraja, Erica Bush, Janet Poole, Dinesh Khanna

In order to predict long-term loads on offshore wind turbines while evaluating ultimate limit states for design, one usually needs to carry out time-domain turbine response simulations. The accuracy of such predictions depends on proper modeling of the inflow turbulence and wave processes as well as of the turbine, the support structure, and the foundation. In order to represent realistic turbine response dynamics for monopile-supported wind turbines common in shallow waters, it is important that the soil-foundation-structure system is described by engineering models routinely used in practice. For the foundation, alternative models may be used that account for soil properties and nonlinear pile behavior under lateral load. The objective of this study is to investigate the effect of alternative monopile foundation models of shallowwater offshore wind turbines on extreme loads associated with 20-year return periods needed during design. Fixed-base, apparent fixity, coupled springs, and distributed springs foundation models are compared. We employ a utility-scale 5MW offshore wind turbine model with a 90meter hub height in stochastic simulations; the turbine is assumed to be sited in 20 meters of water. Selected 20-year wind speed and wave height combinations are employed as we study comparative response statistics, power spectra, and probability distributions of extreme loads for the fixed-base and the different flexible foundation models. A discussion on the varying dynamics, on short-term response statistics, and on extrapolated long-term loads from limited simulation is presented. Sea states involving wind speeds close to the turbine’s rated wind speed are found to control 20-year loads, and the flexible foundation models are found to experience higher extreme loads than the fixed-based case. Overall, the three flexible foundation models appear to yield fairly similar long-term loads computed based on an Inverse FORM (First-Order Reliability Method) approach for the selected turbine and soil profile used in this study. INTRODUCTION Characteristic or nominal loads for the design of wind turbines in ultimate limit states are generally established by employing time-domain aeroelastic response simulations. The accuracy of derived loads depends on the number of simulations and on how realistically the models used to represent the turbine, support structure, and foundation describe the true structural response. One potential shortcoming in modeling offshore wind turbine foundations relates to their flexibility. A single pile (often referred to as a monopile) is the most common type of foundation used today for offshore wind turbines; the support structure connects to such a pile foundation that extends some depth below the mud line. We present four different foundation models. The fixed-base (FB) model is the simplest of the four and assumes a prefectly rigid connection of the 2558 Structures 2009: Don't Mess with Structural Engineers © 2009 ASCE

The objective of this study is to investigate what effect the use of alternative models for monopile pile foundations for shallow-water offshore wind turbines has on extreme loads associated with long return periods that are needed during design. We employ a utility-scale 5MW offshore wind turbine model with a 90-meter hub height in stochastic simulations; the turbine is assumed to be sited in 20 meters of water. Selected 20-year wind-wave combinations are employed as we study comparative time histories, power spectra, response statistics, and probability distributions of extreme loads for fixed-base and flexible foundation models. Two alternative flexible foundation models are considered and longterm loads are studied in comparison with the use of a fixed base model. A discussion on the varying dynamics, on short-term response statistics, and on extrapolated long-term loads from limited simulation is presented. It is shown that root-mean-square (RMS) tower loads are higher for the flexible foundation models than for the fixed-based one. This is due to the smaller stiffnesses of these models. Extreme loads are also higher for the flexible foundation models though not to the same degree as the RMS loads. Seastates involving wind speeds close to the rated wind speed control long-term 20-year loads which can be as much as 15% higher for the flexible foundation models compared to the fixed-base one.

The objective of this study is to investigate the effect of alternative monopile foundation models for shallow-water offshore wind turbines on extreme loads associated with 20-year return periods. Foundation models with tower base fixed at the mudline, with apparent fixity points below the mudline, with coupled transverse and lateral springs at the mudline, and with distributed springs over the entire penetration depth of the monopile are compared. We employ a utility-scale 5 MW offshore wind turbine model with a 90-meter hub height in stochastic simulations; the turbine is sited in 20 meters of water. Selected 20-year wind speed and wave height combinations are employed as we study comparative response statistics, power spectra, and probability distributions of extreme loads for the fixed-base and the three different flexible foundation models. A discussion on the varying dynamics, on short-term response statistics, and on extrapolated long-term loads from limited simulation is presented. Sea states involving wind speeds close to the turbine’s rated wind speed are found to control 20-year loads, and the flexible foundation models are found to experience higher extreme loads than the fixed-based case. Overall, the three flexible foundation models appear to yield similar long-term loads based on an Inverse FORM (First-Order Reliability Method) approach for the selected turbine and soil profile used in this study.Copyright © 2009 by ASME

In evaluating ultimate limit states for design, time-domain aeroelastic response simulations are typically carried out to establish extreme loads on offshore wind turbines. Accurate load prediction depends on proper modeling of the wind turbulence and the wave stochastic processes as well as of the turbine, the support structure, and the foundation. One method for modeling the support structure is to rigidly connect it to the seabed; such a foundation model is appropriate only when the sea floor is firm (as is the case for rock). To obtain realistic turbine response dynamics for softer soils, it is important that a flexible foundation is modeled. While a single discrete spring for coupled lateral/rotational motion or several distributed springs along the length of the monopile may be employed, a tractable alternative is to employ a fictitious fixed-based pile modeled as an “equivalent” cantilever beam, where the length of this fictitious pile is determined using conventional pile lateral load analysis in combination with knowledge of the soil profile. The objective of this study is to investigate the influence of modeling flexible pile foundations on offshore wind turbine loads such as the fore-aft tower bending moment at the mudline. We employ a utility-scale 5MW offshore wind turbine model with a 90-meter hub height in simulations; the turbine is assumed to be sited in 20 meters of water. For a critical wind-wave combination known to control long-term design loads, we study time histories, power spectra, response statistics, and probability distributions of extreme loads for fixed-base and flexible foundation models with the intention of assessing the importance of foundation model selection. Load distributions are found to be sensitive to foundation modeling assumptions. Extrapolation to rare return periods may be expected to lead to differences in derived nominal loads needed in ultimate limit state design; this justifies the use of flexible foundation models in simulation studies.