OBJECTIVEHand dysfunction is common in systemic sclerosis (SSc). The objective of this study was to evaluate the capacity of autologous Adipose-Derived Regenerative Cells (ADRCs) to improve hand function in SSc patients.METHODSThe STAR Trial was a prospective, randomized, double-blind trial of ADRCs injected into each finger digit of subjects with SSc. The primary endpoint was change in hand function at 24 and 48 weeks assessed using the Cochin Hand Function Scale (CHFS). Secondary endpoint included the change in Health Assessment Questionnaire-Disability Index (HAQ-DI) at 48 weeks. Separate analysis of subjects with diffuse (dcSSc) and limited cutaneous SSc (lcSSc) was pre-specified.RESULTS88 subjects were randomized to ADRCs (n=48; 32 dSSc:16 lcSSc) or Placebo (n=40; 19 dcSSc: 21 lcSSc). The primary end point was numerically higher for the ADRC group but did not achieve statistical significance (8.9±10.5 vs. 11.0±12.5, p= 0.299). For subjects with dcSSc the between group difference for the CHFS at 48 weeks was 6.3 points (nominal p=0.069). The HAQ-DI secondary endpoint exhibited a difference of 0.17 points (nominal p=0.044) for dcSSc group. 52% of ADRC-treated subjects with dcSSc reported improvement greater than the minimal clinically important difference for both CHFS and HAQ-DI compared with 16% in the placebo group (nominal p=0.016). Small volume adipose harvest and ADRC-treatment was well-tolerated.CONCLUSIONWhile the primary end point of this trial was not achieved, efficacy trends were observed in subjects with dcSSc. Adipose harvest and ADRC injection were demonstrated to be feasible. Further clinical trial of this intervention in dcSSc is warranted.

Background:Current treatments for systemic sclerosis-associated interstitial lung disease (SSc-ILD) are characterised by different attributes such as mode of administration, adverse events (AE) and efficacy. Physicians and patients often have different perspectives on treatments, thus shared decision-making between patients and physicians is essential. An understanding of patients’ decision processes when weighing treatment attributes and the trade-offs they are willing to make is important for shared decision-making.Objectives:The study aimed to 1) identify relevant treatment attributes, 2) elicit patient preferences for these attributes and 3) quantify preference as relative attribute importance (RAI; a higher RAI indicates that more of the variability in patients’ responses may be explained by changes in the attribute); and maximum acceptable risk (MAR) of diarrhoea, nausea and/or vomiting (MAR is a trade-off measure that evaluates attributes in risk-equivalences as a unit of measurement).Methods:A discrete choice experiment (DCE) was created, based on a literature review, a patient advisory board, qualitative patient interviews, and a workshop involving SSc-ILD expert physicians. Seven SSc-ILD treatment attributes were identified: 1) mode of administration; 2) shortness of breath; 3) skin tightness; 4) cough; 5) tiredness; 6) risk of gastrointestinal tract (GIT) AEs; and 7) risk of serious and non-serious infections. The levels of AE risk were informed by frequencies observed in clinical trials and patient input during the interviews. The DCE was integrated into an online survey, which asked patients to make repeated choices between two alternatives described by varying levels of included attributes. Patients with SSc-ILD were recruited by physician referral from Switzerland, Norway, France, Germany and the USA. DCE data were analysed using a logit model, and RAI and MAR measures were calculated.Results:A total of 231 patients with physician-confirmed SSc-ILD (mean age 52.6±13.2 years; 54% diagnosed for >5 years) completed the survey. Patients with SSc-ILD mostly preferred twice-daily oral treatments (p<0.001) and infusion every 6–12 months (p<0.001) over monthly infusions. Patients’ choices were mostly affected by the risk of GIT AEs (RAI=25%; 95% CI 22–28%) and risk of infections (RAI=20%; 95% CI 16–24%). Improvements in shortness of breath and type and severity of cough were jointly more important than improvement in skin tightness (p<0.001).Patients accepted an additional 21% risk (95% CI 13–29%) of GIT AEs if they could reduce the frequency of infusions from monthly to 6–12 monthly, or accepted an extra 15% (95% CI 7–23%) increase in risk if changing to an oral treatment twice daily. Among symptoms, an additional 28% (95% CI 20–36%) risk of GIT AEs was considered acceptable if the severity of patients’ persistent cough was reduced to a level that was easier to tolerate, even if it remained persistent. Similarly, a 37% (95% CI 28–46%) increase in the risk of GIT AEs was acceptable if it resulted in breathlessness during routine activities rather than breathlessness at rest. Finally, patients were willing to accept an additional 36% risk (95% CI 27–45%) of GIT AEs if it reduced their risk of non-serious infections from 30% to 15% and of serious infections from 10% to 5%.Conclusion:This is the first study to quantitatively elicit patients’ preferences for attributes of SSc-ILD treatments. Preferences were driven by safety, efficacy and technical considerations. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in routine clinical practice.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Consultant of: Eli Lilly, Grant/research support from: Gruppo Italiano Lotta alla Scleroderma (GILS), Fondazione Italiana per la Ricerca sull’Artrite (FIRA), New Horizon Fellowship, European Scleroderma Trial and Research (EUSTAR), Foundation for Research in Rheumatology (FOREUM)., Sebastian Heidenreich Consultant of: Sebastian Heidenreich, PhD is employed by Evidera Inc, a business unit of PPD. Evidera is a CRO that offers paid research services to pharmaceutical companies., Ashley Duenas Consultant of: Yes. I am an employee of Evidera which received funding from Boehringer Ingelheim for work related to this study., Anna-Maria Hoffmann-Vold Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Merck Sharp & Dohme, Lilly, Consultant of: Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli Grant/research support from: Pfizer Bhering, Yannick Allanore Consultant of: Honorarium received from Boehringer, Medsenic,Sanofi, Menarini, Grant/research support from: Grants received from Alpine, Ose Immunogenetics, Emmanuel Chatelus: None declared, Jörg H.W. Distler Shareholder of: JHWD is stock owner of 4D Science, Consultant of: JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Eric Hachulla: None declared, Vivian Hsu Speakers bureau: I am a speaker for Boehringer Ingelheim Pharmaceuticals, Consultant of: with Boehringer Ingelheim Pharmaceuticals, Grant/research support from: Principal Investigator for several clinical trials, currently with Genentech, Corbus Pharmaceutical, and EICOS, Nicolas Hunzelmann Speakers bureau: Boehringer, Roche, Sanofi, Dinesh Khanna Shareholder of: Eicos Sciences, Inc (less than 5%), Consultant of: Paid Consultant for: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics, Grant/research support from: Research Grant support from: Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer, Employee of: Leadership/Equity position – Chief Medical Officer, CiviBioPharma/Eicos Sciences, Inc – recieves a stipend for role as Chief Medical Officer, which would technically qualify as emplyoment., Marie-Elise Truchetet Speakers bureau: Abbvie, Lilly, Sobi, Boehringer, Paid instructor for: Lilly, Consultant of: UCB, Sobi, Abbvie, Grant/research support from: UCB, Gilead, Ulrich Walker Shareholder of: Bayer, NASDAQ, MSCI-World ETF’s, Speakers bureau: All companies producing pharmaceuticals used in AIDS, Paid instructor for: Roche, Abbvie, Novartis, Consultant of: All companies producing pharmaceuticals used in AIDS, Grant/research support from: Gilead, Abbvie, (in the last two years). Other companies in previous years., Margarida Alves Employee of: Boehringer Ingelheim, Nils Schoof Employee of: Employee of Boehringer Ingelheim International GmbH, Lesley Ann Saketkoo Speakers bureau: Boehringer Ingelheim, Actelion, Janssen, Mallinckrodt, United Therapeutics, Consultant of: Actelion, Boehringer Ingelheim, Bayer, Bristol Meyer Squibb, Corbus, EICOS, Janssen, Horizon, United Therapeutics, Inc, Grant/research support from: Mallinckrodt, United Therapeutics, Oliver Distler Speakers bureau: Boehringer Ingelheim, Medscape, IQone, Roche, Consultant of: OD has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years):Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: Kymera Therapeutics, Mitsubishi Tanabe

BackgroundLenabasum (JBT-101) is a selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses in humans and reduces inflammation and fibrosis in animal models of SSc. It is a synthetic, oral, non-immunosuppressive small molecule. Lenabasum had acceptable safety and tolerability and showed evidence of clinical benefit in diffuse cutaneous SSc (dcSSc) in Phase 2 trial JBT101-SSc-001 (NCT02465437).ObjectivesThe objective of this study was to provide long-term open-label safety and efficacy data in dcSSc subjects who received lenabasum in that trial.MethodsSubjects who completed the double-blind placebo-controlled (DBPC) part of JBT101-SSc-001 were eligible to receive lenabasum 20 mg BID in an open-label extension (OLE).Results36/38 (95%) eligible subjects enrolled in the OLE and 34/36 (94%) were on baseline immunosuppressive drugs. The mean interval off study drug from the end of DBCP dosing to the start of OLE dosing of 9.5 weeks (range 4.7 to 56 weeks). At the time of data cut-off, the duration of OLE dosing was median 51.4 weeks, mean 45 weeks (range 26, 418 weeks), and 19 subjects had completed Week 60. Three subjects discontinued, 2 for AEs and 1 for withdrawal of consent. Adverse events (AEs, n=171) occurred in 33/36 (92%) subjects in the OLE. By maximum severity, 1 (3%) subject had life threatening AE, 3 (8%) subjects had severe AEs, 21 (58%) subjects had moderate AEs and 8 (22%) had mild AEs. Seven (19%) subjects had AEs considered related to lenabasum. The AEs that occurred in ≥10% of subjects (n,% of subjects) were upper respiratory tract infection (8, 22%), urinary tract infection (5, 14%), diarrhoea (4, 11%) and skin ulcers (4, 11%). Mild intermittent dizziness occurred in 3 (8%) subjects. One subject developed renal crisis 7 days after starting 60 mg/day prednisone prescribed by a non-study physician and had 2 severe and 1 life-threatening/serious AEs related to the renal crisis and deemed unrelated to lenabasum. During the OLE, there was improvement in multiple efficacy outcomes from both the study start and the OLE start. For example, in the 25 subjects who had completed OLE Week 52 at the time of data cut-off, the mean (SE) improvements from study start were: ACR CRISS score=56% (9%); modified Rodnan Skin Score=-8.6 (1.5); HAQ-DI=-0.14 (0.11), Physician Global Assessment=-0.9 (0.5), and 5-D Itch Questionnaire=-2.3 (0.8). Forced vital capacity% predicted was stable from study start with mean (SE) change=0.4% (0.7%).ConclusionsIn OLE of Phase 2 trial JBT101-SSc-001, lenabasum continues to have acceptable safety and tolerability in dcSSc with no severe or serious AEs. Multiple efficacy outcomes improved, although open-label nature of dosing with lenabasum is acknowledged. These data support Phase 3 testing of lenabasum for treatment of dcSSc.Disclosure of InterestR. Spiera: None declared, L. Hummers: None declared, L. Chung: None declared, T. Frech: None declared, R. Domsic: None declared, V. Hsu: None declared, D. Furst: None declared, J. Gordon: None declared, M. Mayes Consultant for: Boehringer-Ingelheim, Mitsubishi-Tanabe, Astellas, Roche-Genentech, R. Simms: None declared, E. Lee Employee of: Corbus Pharmaceuticals, Inc., N. Dgetluck Employee of: Corbus Pharmaceuticals, Inc., S. Constantine Employee of: Corbus Pharmaceuticals, Inc., B. White Employee of: Corbus Pharmaceuticals, Inc.

Objective: Sex differences in the brain are traditionally treated as binary. We present new evidence that a continuous measure of sex differentiation of the brain can explain sex differences in psychopathology. The degree of sex-differentiated brain features (ie, features that are more common in one sex) may predispose individuals toward sex-biased psychopathology and may also be influenced by the genome. We hypothesized that individuals with a female-biased differentiation score would have greater female-biased psychopathology (internalizing symptoms, such as anxiety and depression), whereas individuals with a male-biased differentiation score would have greater male-biased psychopathology (externalizing symptoms, such as disruptive behaviors). Method: Using the Philadelphia Neurodevelopmental Cohort database acquired from database of Genotypes and Phenotypes, we calculated the sex differentiation measure, a continuous data-driven calculation of each individual's degree of sex-differentiating features extracted from multimodal brain imaging data (magnetic resonance imaging [MRI] /diffusion MRI) from the imaged participants (n = 866, 407 female and 459 male). Results: In male individuals, higher differentiation scores were correlated with higher levels of externalizing symptoms (r = 0.119, p = .016). The differentiation measure reached genome-wide association study significance (p < 51*10(-8)) in male individuals with single nucleotide polymorphisms Chromsome5:rs111161632:RASGEF1C and Chromosome19:rs75918199:GEMIN7, and in female individuals with Chromosome2:rs78372132:PARD3B and Chromosome15:rs73442006:HCN4. Conclusion: The sex differentiation measure provides an initial topography of quantifying male and female brain features. This demonstration that the sex of the human brain can be conceptualized on a continuum has implications for both the presentation of psychopathology and the relation of the brain with genetic variants that may be associated with brain differentiation.

Background Few small-sized observational studies have suggested that rituximab might be a promising treatment in systemic sclerosis (SSc) Objectives To evaluate the outcomes of SSc-patients receiving in routine care Rituximab Methods Retrospective longitudinal multicenter observational study which included SSc-patients treated with rituximab upon the decision of their physician within the framework of EUSTAR. We interrogated the participating centres and EUSTAR database to determine epidemiological and clinical characteristics, the indication for initiating the treatment, and the following parameters at baseline and at the last visit under treatment: modified Rodnan Skin Score (mRSS), joint, lung and gastrointestinal involvements, treatment, laboratory tests and safety events. Results 248 patients were included: 70 (28%) men, mean age: 51±13 years, mean disease duration: 7±7 years; 150 (65%) had diffuse cutaneous-SSc, 54% were positive for anti-topoisomerase and 71% had lung fibrosis. Overlap disease was noticed in 62 patients (26%) including 23 with rheumatoid arthritis. The indication for the treatment was lung involvement (56%) followed by articular (42%) and skin involvements (30%). At baseline, 175 patients were treated with steroids and 132 with DMARDs. Mean follow-up was 2.4 (±1.9) years. In the whole sample, mRSS decreased from 15±11 to 10±8 (p<0.01). For SSc-patients treated for lung with baseline FVC <70%, FVC improved from 56±9% to 59±12%; p=0.02. In patients with articular involvement (n=83), tender joint and swollen joint counts decreased from 9±7 to 4±6 and from 3±5 to 1±3, respectively (p<0.01). In the whole population, 45 patients could stop steroids and mean dose decreased from 10 mg to 7 mg in the other. During the follow-up, 78 (31%) patients had side effects including 35 (14%) with severe side effects leading to discontinuation of the treatment in 10%. Six deaths were recorded (1 heart failure, 1 sepsis, 2 respiratory insufficiencies, 2 sudden deaths). 76 patients had infection, requiring hospitalisation in 20 patients. Conclusions In this study, skin, lung and joint involvement appeared to improve under rituximab. Infections and other severe adverse events were frequently reported. A comparative study including control patients from EUSTAR centres is ongoing. Disclosure of Interest M. Elhai: None declared, O. Distler Grant/research support from: Actelion, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Sanofi, Sinoxa and UCB in the area of potential treatments of scleroderma and its complications, V. Smith : None declared, M. Matucci-Cerinic: None declared, J. J. Alegre-Sancho : None declared, M.-E. Truchetet: None declared, Y. Braun-Moscovici: None declared, F. Iannone: None declared, F. Chotchaeva: None declared, A. Lescoat : None declared, E. Siegert : None declared, I. Castellví: None declared, P. Airò : None declared, S. Vettori: None declared, E. Hachulla: None declared, A. Erler : None declared, L. Ananieva : None declared, M. Krusche: None declared, F. López-Longo : None declared, J. Distler : None declared, N. Hunzelmann : None declared, A.-M. Hoffmann-Vold : None declared, V. Riccieri: None declared, V. Hsu: None declared, M. Pozzi: None declared, C. Ancuta : None declared, E. Rosato : None declared, C. Mihai: None declared, M. Kuwana: None declared, Y. Allanore Grant/research support from: Actelion, Bayer, Boehringer Ingelheim, ChemomAb, Genentech/Roche, Inventiva, Pfizer, Sanofi, Servier, in the area of potential treatments of scleroderma and its complications.

Background: Quantification of facial dynamic motion is paramount for improving cosmetic and reconstructive surgical outcomes. The authors introduce digital image correlation using speckle tracking photogrammetry and Aramis software (GOM mbH, Braunschweig, Germany) to study facial dynamics and demonstrate its application in quantifying botulinum toxin efficacy. Methods: Fourteen subjects were evaluated using a dual camera system and three-dimensional optical analysis. Using Aramis software, the anatomic regions of the glabella, forehead, and total face were identified and highlighted. Tissue strain, defined as either compression or stretch, was measured within these regions over 36 frames during brow furrowing. Each patient was measured before and 2 weeks after injection of 20 units of onabotulinumtoxinA in the glabella. Average stretch and compression in treated areas were analyzed across all available frames. Results were compared using a Wilcoxon signed rank test. Results: After neurotoxin injection, average vertical stretch of the glabella during brow furrowing decreased from 2.51 percent to 1.15 percent (p < 0.05), and average vertical stretch in the forehead decreased from 6.73 percent to 1.67 percent (p < 0.05). Horizontal compression in the glabella decreased from 9.11 percent to 2.60 percent (p < 0.05) and from 4.83 percent to 0.83 percent (p < 0.05) in the forehead. Total facial major strain decreased from 4.41 percent to 3.05 percent (p < 0.05), and total facial minor strain decreased from 5.01 percent to 3.51 percent (p < 0.05). Conclusions: The authors introduce digital image correlation as a novel technology for measuring dynamic rhytid and neurotoxin efficacy. This technique allows for advancements in the study of dynamic aging and neuromuscular disorders. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II.

Background: Complex regional pain syndrome (CRPS) is a painful condition with approximately 50,000 annual new cases in the United States. It is a major cause of work-related disability, chronic pain after limb fractures, and persistent pain after extremity surgery. Additionally, CRPS patients often experience cognitive changes, anxiety, and depression. The supraspinal mechanisms linked to these CRPS-related comorbidities remain poorly understood.Methods: The authors used a previously characterized mouse model of tibia fracture/cast immobilization showing the principal stigmata of CRPS (n = 8 to 20 per group) observed in humans. The central hypothesis was that fracture/cast mice manifest changes in measures of thigmotaxis (indicative of anxiety) and working memory reflected in neuroplastic changes in amygdala, perirhinal cortex, and hippocampus.Results: The authors demonstrate that nociceptive sensitization in these mice is accompanied by altered thigmotactic behaviors in the zero maze but not open field assay, and working memory dysfunction in novel object recognition and social memory but not in novel location recognition. Furthermore, the authors found evidence of structural changes and synaptic plasticity including changes in dendritic architecture and decreased levels of synaptophysin and brain-derived neurotrophic factor in specific brain regions.Conclusions: The study findings provide novel observations regarding behavioral changes and brain plasticity in a mouse model of CRPS. In addition to elucidating some of the supraspinal correlates of the syndrome, this work supports the potential use of therapeutic interventions that not only directly target sensory input and other peripheral mechanisms, but also attempt to ameliorate the broader pain experience by modifying its associated cognitive and emotional comorbidities.

In the setting of recurrent infection and multiple failed reconstruction attempts, the choice of the ideal reconstructive material for salvage cranioplasty remains a source of controversy in the literature. The purpose of this study is to establish the safety and utility of antibiotic-impregnated polymethyl methacrylate (PMMA) for salvage cranioplasty. A prospectively maintained database of all patients who underwent salvage cranioplasty using vancomycin and tobramycin-impregnated methyl methacrylate from January 2011 to July 2013 was reviewed. Vancomycin and tobramycin were mixed in PMMA, which was then applied to a rigidly fixed titanium mesh for reconstruction. Patients' demographics, indications, and outcomes of this technique were evaluated. Nine patients (mean age: 47 years) underwent vancomycin and tobramycin-impregnated PMMA reconstruction with a mean follow-up of 9.3 months (range 3.5-23 months). On average, these patients underwent 4 procedures (range: 1-15), which included repeat craniotomy, debridement for infection, and failed reconstructions over the course of 3.6 years (range: 7 months to 14 years) before salvage cranioplasty. All patients required salvage cranioplasty due to infection, with the most common bacteria isolated in culture being Propionibacterium acnes (n = 3), multiresistant coagulase-negative Staphylococcus (n = 3), methicillin-resistant Staphylococcus aureus (n = 2), and Enterobacter (n = 2). The average size of the craniectomy defect was 130 cm(2), and there were no incidences of postoperative infection, postoperative complications, or need for revisions. To conclude, in short-term follow-up, vancomycin and tobramycin-impregnated PMMA reconstruction appears safe and effective in salvage cranioplasty. Our early report represents a proof of conceptthe true test is whether these short-term successes translate to stable long-term results.

852 October 2014 C regional pain syndrome (CRPS) is a painful, disabling, and often chronic condition with an estimated 50,000 new cases in the United States each year.1 It is characterized by severe pain-related changes (allodynia and hyperalgesia), trophic changes (abnormalities in hair and nail growth), neurovascular abnormalities (abnormal sweating, edema, and skin discoloration), and motor changes (tremor).2–4 Despite the fact that CRPS has been a documented clinical entity for at least 150 yr, we have only a partial understanding of the supporting mechanisms, and no broadly effective treatments. Current therapies including physical, interventional, pharmacological, rehabilitative, and alternative are limited in their effectiveness, and none are curative,5,6 leaving more than 80% of chronic CRPS patients severely disabled.7 Similar to other chronic pain conditions, CRPS encompasses neurocognitive changes as well as alterations in mood and anxiety that affect quality of life, level of disability, and need for additional health care.8,9 More broadly, a recent What We Already Know about This Topic

Background: The aim of this study is to evaluate and quantify dynamic soft-tissue strain in the human face using real-time 3-dimensional imaging technology. Methods: Thirteen subjects (8 women, 5 men) between the ages of 18 and 70 were imaged using a dual-camera system and 3-dimensional optical analysis (ARAMIS, Trilion Quality Systems, Pa.). Each subject was imaged at rest and with the following facial expressions: (1) smile, (2) laughter, (3) surprise, (4) anger, (5) grimace, and (6) pursed lips. The facial strains defining stretch and compression were computed for each subject and compared. Results: The areas of greatest strain were localized to the midface and lower face for all expressions. Subjects over the age of 40 had a statistically significant increase in stretch in the perioral region while lip pursing compared with subjects under the age of 40 (58.4% vs 33.8%, P = 0.015). When specific components of lip pursing were analyzed, there was a significantly greater degree of stretch in the nasolabial fold region in subjects over 40 compared with those under 40 (61.6% vs 32.9%, P = 0.007). Furthermore, we observed a greater degree of asymmetry of strain in the nasolabial fold region in the older age group (18.4% vs 5.4%, P = 0.03). Conclusions: This pilot study illustrates that the face can be objectively and quantitatively evaluated using dynamic major strain analysis. The technology of 3-dimensional optical imaging can be used to advance our understanding of facial soft-tissue dynamics and the effects of animation on facial strain over time.

BackgroundBreast reconstruction is an integral component of breast cancer treatment, often aiding in restoring a patient’s sense of femininity. However, many patients choose to have subsequent cosmetic surgery. The purpose of this study is to investigate the reasons that motivate patients to have cosmetic surgery after breast reconstruction. MethodsThe authors performed a retrospective study examining patients who had breast reconstruction and subsequent cosmetic surgery at the University of Pennsylvania Health System between January 2005 and June 2012. This cohort received a questionnaire assessing the influences and impact of their reconstructive and cosmetic procedures. ResultsA total of 1,214 patients had breast reconstruction, with 113 patients (9.3%) undergoing cosmetic surgery after reconstruction. Of 42 survey respondents, 35 had autologous breast reconstruction (83.3%). Fifty-two cosmetic procedures were performed in survey respondents, including liposuction (26.9%) and facelift (15.4%). The most common reason for pursuing cosmetic surgery was the desire to improve self-image (n = 26, 61.9%), with 29 (69.0%) patients feeling more self-conscious of appearance after reconstruction. Body image satisfaction was significantly higher after cosmetic surgery (P = 0.0081). Interestingly, a multivariate analysis revealed that patients who experienced an improvement in body image after breast reconstruction were more likely to experience a further improvement after a cosmetic procedure (P = 0.031, OR = 17.83). Patients who were interested in cosmetic surgery prior to reconstruction were also more likely to experience an improvement in body image after cosmetic surgery (P = 0.012, OR = 22.63). ConclusionCosmetic surgery may improve body image satisfaction of breast reconstruction patients and help to further meet their expectations.

Background CD19+ B cells may play a role in the pathogenesis of SSc. MEDI-551 is a humanized afucosylated IgG1κ monoclonal antibody that binds to CD19 and depletes B cells. Therefore, MEDI-551 may show activity in patients with SSc. Objectives Safety and tolerability of escalating single IV doses of MEDI-551 in adults with SSc who have moderate skin thickening. PK, PD, immunogenicity, and disease activity are also assessed. Methods A phase 1, randomized, placebo-controlled study in adults with SSc with moderate skin thickening (modified Rodnan Skin Score [mRSS] ≥2) in an area suitable for repeat biopsy. Subjects received 1 of 5 single IV doses of MEDI-551 (0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo (PBO). Cohort 1 (0.1 mg/kg; n=1) received MEDI-551 in an open-label manner; cohort 2 (0.3 mg/kg; n=5) was randomized 4:1 to receive MEDI-551 or PBO; cohorts 3 and 4 (1.0, 3.0 mg/kg; n=7) were randomized 6:1; and cohort 5 (10 mg/kg; n=8) was randomized 7:1. AEs were monitored. Blood was collected for PK, PD, and anti-drug antibodies (ADAs). All subjects were followed until the B-cell count in peripheral blood returned to baseline (BL). Results All subjects (MEDI-551 n=24; PBO n=4) completed primary follow up period (Day 85) of the study; there were no discontinuations for any reason. Most subjects were white (86%) and female (68%); median age 48.5y and median disease duration 4.65y from first non-Raynaud9s symptoms. 86% subjects had diffuse cutaneous SSc; median mRSS was 22 (range 9–43). Follow-up is ongoing. As of 31Dec13, median duration in study ranged from 401d–1364d for MEDI-551 subjects and was 622d for PBO. Related AEs occurred only with MEDI-551; most were single events except infusion-related reaction (n=4; only observed in subjects without pre-medication) and cough (n=2). No serious AEs occurred in the PBO group. 15 SAEs occurred in 6 subjects in the MEDI-551 group; 2 (supraventricular tachycardia, subclavian vein thrombosis) were considered possibly related to MEDI-551. 1 subject in the 3.0 mg/kg group died due to worsening of scleroderma renal disease (not considered MEDI-551 related). PK was nonlinear after MEDI-551 administration (0.1–10.0 mg/kg). The t1/2 were similar (11.2–13.5d) for doses ≥1.0 and shorter for doses <1.0 mg/kg (6.8–7.1d). ADAs were detected in 4 subjects who received MEDI-551; all had reduced serum MEDI-551 levels compared to those without ADAs in the same dose group. Following MEDI-551 infusion, B-cell counts were depleted ∼90% from BL in all dose groups by Day 57. B-cell depletion was maintained for ≥6mos in 1 (17%) subject in the 1.0 mg/kg group, 3 (50%) in the 3.0 mg/kg group, and 6 (86%) in the 10 mg/kg group. Median mRSS decreased from BL (-5; range -14 to 2) with MEDI-551 by Day 85 but increased with PBO (2.5; range -4 to 8) suggesting clinical activity on skin thickness by MEDI-551. Conclusions The safety profile of MEDI-551 at single IV doses ranging from 0.1 to 10.0 mg/kg supports further clinical development. Rapid sustained B-cell depletion was observed following single IV infusion with 3.0 and 10.0 mg/kg MEDI-551. Clinical activity was suggested by decreased mRSS with MEDI-551. Acknowledgements This study was sponsored by MedImmune. Disclosure of Interest E. Schiopu Grant/research support: Actelion, InterMune, MedImmune, Pfizer, United Therapeutics, Consultant for: Sobi, Inc., Paid instructor for: United Therapeutics, Speakers bureau: United Therapeutics, Actelion, S. Chatterjee Grant/research support: MedImmune, V. Hsu Grant/research support: MedImmune, A. Flor Shareholder of: AstraZeneca, Employee of: MedImmune, D. Pavlovic Shareholder of: AstraZeneca, Employee of: MedImmune, K. Patra Shareholder of: AstraZeneca, Employee of: MedImmune, J. Li Shareholder of: AstraZeneca, Employee of: MedImmune, K. McKeever Shareholder of: AstraZeneca, Employee of: MedImmune, R. Herbst Shareholder of: AstraZeneca, Employee of: MedImmune DOI 10.1136/annrheumdis-2014-eular.5908

OBJECTIVES We sought to examine the relationship between measures of ILD severity and PH in patients with SSc. METHODS We identified 55 subjects from 12 PHAROS sites with RHC-proven PH and HRCT evidence of ILD. Subjects with PH due to left heart disease were excluded. Baseline HRCT scans were scored by a standardised system that graded severity of ILD. Summary statistics were generated for baseline characteristics. Spearman correlation and linear regression were used to examine relationships between ILD and PH severity variables. RESULTS The majority of subjects were white women; nearly half had limited cutaneous SSc. Most subjects were New York Heart Association functional class II or III. Pulmonary function testing revealed moderate restriction (mean FVC 64.3 ± 17.2% predicted) with severe reduction in diffusing capacity (mean DLco 34.2 ± 13.3% predicted). RHC demonstrated mild to moderate PH (mean PAP 35 ± 9 mmHg, mean PVR 5.1 ± 3.7 WU). There was no correlation between severity of ILD (by either HRCT or PFT) and cardiac haemodynamic parameters of PH. CONCLUSIONS No association between severity of ILD and cardiac haemodynamic profiles were identified in this cohort. We believe this underscores the complex nature of PH and ILD in individuals with SSc. We do suspect that some individuals with SSc-ILD will also have concomitant pulmonary vascular disease but simple assessments to grade severity of ILD - by PFT or HRCT estimates of ILD extent - are likely not enough to reliably distinguish between PAH versus PH-ILD. Further research into how to distinguish and manage these subsets is warranted.

Background: The squamosal suture is markedly different from the major calvarial sutures of the human skull. The unique properties of the suture are a result of the complex developmental biology of the temporal bone and biomechanical force exerted by surrounding structures. The dysmorphic effects of premature fusion of the suture, and possible treatment strategies in cases of synostosis, have received only brief description in the literature. Methods: A retrospective case series was performed. The study included patients evaluated by one of the senior authors (S.P.B., R.R.R., and D.J.S.) between 1993 and 2009. All pertinent patient data including inpatient and outpatient charts, photographic records, and radiographic scans were reviewed. Any management performed under the direction of a craniofacial surgeon was documented—including orthotic helmet therapy and operative management. Results: The study included 14 patients. Synostosis of the squamosal suture was noted to occur either in an isolated fashion or in the setting of other craniofacial malformations. Patients with isolated squamosal synostosis often suffered from a deformity that was mild in severity and tended to improve with time. However, when occurring in the setting of other forms of craniosynostosis, the deformity was often progressive, and transcranial surgery was frequently required. Conclusions: Synostosis of the squamosal suture can result in, or contribute to, significant craniofacial dysmorphism. The optimal form of therapy for this disorder is evolving.

The concept of aging and the mechanisms responsible for soft tissue aging have become progressively more important as the world's population ages and demands a higher quality of life. Although molecular mechanisms of aging have been evaluated in model organisms, specific genomic, genetic, and epigenetic modifications that can be translated to normal human tissue aging have yet to be identified. We propose that adipose tissue is an excellent model with which to investigate molecular aging pathways. The goal of this study is to demonstrate that primary human adipose tissue can serve as a model of human aging, and further, can be used to detect differences in genomic transcriptional profiling between cell types in adipose tissue as well as between youthful and older age groups.Subcutaneous adipose tissue was excised during cosmetic procedures from healthy patients. Adipocytes and stromal vascular fractions from the anterior abdomen were isolated from 3 young (26-39 years) and 3 old (52-64 years) patients and analyzed for genome-wide transcriptional differences between varying ages and cell types using the Affymetrix GeneChip Human Gene Chip 1.0ST.Genes specific to adipocytes were more highly expressed in adipocytes than in stromal vascular fractions, validating that adipose tissue should be examined in a cell-specific manner. An increase in overall gene expression was observed among patients in the older age group, consistent with senescence-related chromatin dysregulation. Principal components analysis revealed no clear delineation between age groups and a clear separation by cell type. Analysis of variance revealed cell type as the most significant variable in transcriptional differences, whereas age-related differences were a distant second. Gene Ontology categories of the most significantly modified genes included RNA splicing and mRNA metabolism, plasma membrane, and mitochondrial metabolism.Primary adipose tissue is an effective model for the study of the molecular mechanisms of human aging. Our findings are consistent with the hypothesis that epigenetic modifications play a more important role than transcriptional modifications in early human adipose tissue aging. Our future studies will examine the contribution of specific epigenetic markers to human adipose tissue aging and promise to advance approaches in regenerative medicine, and the prevention and treatment of aging.

BACKGROUND:The concept of aging and the mechanisms responsible for soft tissue aging have become progressively more important as the world's population ages and demands a higher quality of life. Although molecular mechanisms of aging have been evaluated in model organisms, specific genomic, genetic, and epigenetic modifications that can be translated to normal human tissue aging have yet to be identified. We propose that adipose tissue is an excellent model with which to investigate molecular aging pathways. The goal of this study is to demonstrate that primary human adipose tissue can serve as a model of human aging, and further, can be used to detect differences in genomic transcriptional profiling between cell types in adipose tissue as well as between youthful and older age groups.METHODS:Subcutaneous adipose tissue was excised during cosmetic procedures from healthy patients. Adipocytes and stromal vascular fractions from the anterior abdomen were isolated from 3 young (26-39 years) and 3 old (52-64 years) patients and analyzed for genome-wide transcriptional differences between varying ages and cell types using the Affymetrix GeneChip Human Gene Chip 1.0ST.RESULTS:Genes specific to adipocytes were more highly expressed in adipocytes than in stromal vascular fractions, validating that adipose tissue should be examined in a cell-specific manner. An increase in overall gene expression was observed among patients in the older age group, consistent with senescence-related chromatin dysregulation. Principal components analysis revealed no clear delineation between age groups and a clear separation by cell type. Analysis of variance revealed cell type as the most significant variable in transcriptional differences, whereas age-related differences were a distant second. Gene Ontology categories of the most significantly modified genes included RNA splicing and mRNA metabolism, plasma membrane, and mitochondrial metabolism.CONCLUSIONS:Primary adipose tissue is an effective model for the study of the molecular mechanisms of human aging. Our findings are consistent with the hypothesis that epigenetic modifications play a more important role than transcriptional modifications in early human adipose tissue aging. Our future studies will examine the contribution of specific epigenetic markers to human adipose tissue aging and promise to advance approaches in regenerative medicine, and the prevention and treatment of aging.

Fat grafting is a common reconstructive and aesthetic procedure with extensive clinical applications. Recently, significant strides have been made in investigating the biology behind the success of this procedure. Surgeons and scientists alike have advanced this field by innovating fat graft harvesting and injection techniques, expanding the use of adipose tissue and its stem cell components, and broadening our understanding of the viability of fat grafting at the molecular and cellular levels. The objectives of this review are to (1) discuss the clinical applications of fat grafting, (2) describe the cellular biology of fat and the optimization of fat graft preparation, (3) illustrate the significance of adipose-derived stem cells and the potentiality of fat cells, (4) highlight the clinical uses of adipose-derived stem cells, and (5) explore the current and future frontiers of the study of fat grafting. Although collaborative knowledge has increased exponentially, many of the biological mechanisms behind fat grafting are still unknown. Plastic surgeons are in a unique position to pioneer both the scientific and clinical frontiers of fat grafting and to ultimately further this technology for the benefit of our patients.