Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair.

The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones. Cells expressing either of these BRCA1-BARD1 separation-of-function alleles are hypersensitive to DNA-damaging agents. Furthermore, we demonstrate that BRCA1-BARD1 ligase is not only required for DNA resection during homology-directed repair (HDR) but also contributes to later stages for HDR completion. Altogether, our findings reveal crucial, previously unrecognized roles of BRCA1-BARD1 ligase activity in genome repair via HDR, settle prior controversies regarding BRCA1-BARD1 ligase functions, and catalyze new efforts to uncover substrates related to tumor suppression.

High-Efficiency Plasmid DNA Transformation in Yeast.

Transformation of DNA into cells of the budding yeast Saccharomyces cerevisiae and other industrially important yeasts is most commonly performed using chemical-based methods. Current protocols typically involve exposure of the cells to lithium ions in a solution containing the crowding agent polyethylene glycol (PEG), often in conjunction with other reagents such as dimethyl sulfoxide (DMSO) that promote destabilization of the cell wall and/or cell envelope. Recent work has demonstrated that it is possible to achieve high transformation efficiencies with early stationary phase cells, i.e., small overnight liquid cell cultures, using methods that are rapid and readily scalable for high-throughput projects. Herein, we describe carrier DNAs, chemical reagents, and cell growth media that permit transformation of yeast cells with either plasmids or linear DNA fragments with high efficiency.

Augmented Reality and Plastic Surgery Training: A Qualitative Study.

Background and objective The coronavirus disease 2019 (COVID-19) pandemic has led to many challenges in face-to-face teaching and training in plastic surgery. However, it has also proved to be an incubator for many technological solutions. Augmented reality (AR) platforms may offer a safe, equitable, and efficient means to provide training in plastic surgery. This study aimed to explore the user's experience of AR as an educational intervention during the COVID-19 pandemic in the United Kingdom (UK). Materials and methods The Proximie® AR platform (Proximie Limited, London, UK) has been in use in a UK plastic surgical department for facilitating webinars, visual libraries, and streamed procedures. The experience of a range of trainers and trainees was qualitatively explored through 10 individual interviews. Data-emergent theme analysis was also performed. Results AR was well-received in the context of COVID-19 and training in general as a means to enable theatre access, and visual revision, remotely. The potential for its use in remote coaching and telementoring was also discussed. Recommendations were made by the users to optimise the experience both from the trainer and learner perspectives. Data were presented pertaining to the following themes: surgical AR as a substitute for hands-on learning; surgical AR and theoretical learning; considerations specific to streamed procedures using Proximie®; considerations in the use of technology in general. Conclusion Harnessing novel technologies in surgical education offers an exciting opportunity, fast-tracked by COVID-19, but applicable beyond it. Though this study includes a small sample size, its findings suggest that AR platforms may offer a uniquely interactive remote educational experience in surgical training. Strategies and suggestions for its use are discussed, as well as broader considerations in using technology in surgical education.

Tracheostomy in the coronavirus disease 2019 patient: evaluating feasibility, challenges and early outcomes of the 14-day guidance.

OBJECTIVES: To report feasibility, early outcomes and challenges of implementing a 14-day threshold for undertaking surgical tracheostomy in the critically ill coronavirus disease 2019 patient. METHODS: Twenty-eight coronavirus disease 2019 patients underwent tracheostomy. Demographics, risk factors, ventilatory assistance, organ support and logistics were assessed. RESULTS: The mean time from intubation to tracheostomy formation was 17.0 days (standard deviation = 4.4, range 8-26 days). Mean time to decannulation was 15.8 days (standard deviation = 9.4) and mean time to intensive care unit stepdown to a ward was 19.2 days (standard deviation = 6.8). The time from intubation to tracheostomy was strongly positively correlated with: duration of mechanical ventilation (r(23) = 0.66; p < 0.001), time from intubation to decannulation (r(23) = 0.66; p < 0.001) and time from intubation to intensive care unit discharge (r(23) = 0.71; p < 0.001). CONCLUSION: Performing a tracheostomy in coronavirus disease 2019 positive patients at 8-14 days following intubation is compatible with favourable outcomes. Multidisciplinary team input is crucial to patient selection.

Technical refinements of the free medial sural artery perforator (MSAP) flap in reconstruction of multifaceted ankle soft tissue defects.

BACKGROUND: Peri-ankle defects are difficult to reconstruct due to sharp contours, thin skin, aesthetic value, function and footwear impact. The medial sural artery perforator flap (MSAP) is increasing in popularity as a thin and pliable flap. This study aims to demonstrate its versatility in reconstructing defects around the ankle area and our approach to insetting these flaps in difficult areas around the ankle without the need for subsequent flap revisions. METHODS: A retrospective review of the senior author's series of peri-ankle reconstructions using the MSAP flap was undertaken. RESULTS: Between 2011-2015, 15 patients underwent peri-ankle reconstruction with the MSAP flap. There were 4 dorsal foot, 4 medial malleolar, 4 lateral malleolar, and 3 tendo-achilles defects. All flaps in this series survived. There was one episode of partial flap necrosis in one patient and no incidences of donor site dehiscence. All patients returned to full ambulation and none required subsequent flap revision. CONCLUSIONS: The MSAP flap offers the benefits of a fasciocutaneous flap, whilst providing a thin, pliable, single stage and robust reconstruction for peri-ankle defects, with a cosmetically ideal donor site.

Risk factors and timing of postoperative hematomas following microvascular breast reconstruction: A prospective cohort study.

BACKGROUND: Microvascular free tissue transfer has become the gold standard for breast reconstruction. While safe and reliable, there are operative complications, with hematomas developing under the free flap among the more common. These can compromise flap viability, lead to hemodynamic instability and infection. This study aims to identify predictors of hematomas following free-flap breast reconstruction. METHODS: A prospective study was undertaken of patients undergoing autologous free-flap breast reconstruction over a 4-year period. Precise times to hematoma formation, age, arterial and venous anastomosis time, and anastomosis length were recorded and analyzed for association with time to hematoma formation. RESULTS: One thousand two hundred twelve flaps were undertaken in 1,070 patients during the period of review. Seventy-one (5.8%) flaps were taken back to theater for hematomas. Immediate reconstruction had a significantly higher hematoma rate compared to delayed reconstruction 7.4% versus 5.2% (p < .001). It is noted that there were two main peaks for time to develop hematomas-less than 4 hr postsurgery and between 12 and 15 hr postsurgery. CONCLUSION: Hematomas are a complication, which must be managed with prompt return to theater to ensure flap salvage and patient stabilization. Predictors for hematoma are presented, with hematomas most likely encountered within the first 12 hr of surgery.

Ankylosing Spondylitis Response to TNF Inhibition Is Gender Specific: A 6-Year Cohort Study

Aim Recent studies have suggested gender-specific differences with respect to both baseline disease activity and severity in ankylosing spondylitis (AS). Tumour necrosis factor inhibitors (TNFi) have shown significant benefit in AS but there may be gender-specific differences regarding responses to TNFi therapy. Methods AS patients with active disease despite adequate trials of NSAIDs were commenced on TNFi and followed in a biologic clinic between 2004 and 2011. Response to treatment was measured based on clinical and serological outcomes. Baseline radiographic data were also collected where available. Results 147 AS patients commenced TNFi therapy and were followed in a biologic clinic between 2004 and 2011. One-hundred and six (72%) of the patients were male and 90 (61%) were current or ex-smokers. The specific TNFi prescribed included etanercept (74 patients, 50.3%), adalimumab (51 patients, 34.7%), infliximab (21 patients, 14.2%) and golimumab (1 patient, 0.7%). The median mSASSS score was 11 (interquartile range 5-35). At baseline, the metrology indices (BASMI) were significantly lower in women (2.6 v 4; p=0.01) but all other clinical indices were similar. At 3 months, female patients had significantly worse median disease activity and functional indices (BASDAI: 4 v 2; p<0.01; BASFI: 3 v 2; p=0.03) than male patients. In addition, females had higher median ESR (19 v 6; p<0.01) which correlated with their disease activity indices (r=0.42, p=0.02). Discussion Despite similar disease activity at baseline, post-TNFi therapy women had significantly higher disease activity. Furthermore, ESR levels in women during therapy correlated with their clinical disease activity scores. Further exploration of these gender-specific differences is crucial for a greater understanding of the pathogenesis of AS as well as development of targeted therapies.

Secukinumab provides sustained PASDAS-defined remission in psoriatic arthritis and improves health-related quality of life in patients achieving remission: 2-year results from the phase III FUTURE 2 study.

BACKGROUND: Secukinumab has demonstrated sustained improvement in the signs and symptoms of psoriatic arthritis (PsA) over 2 years in the FUTURE 2 study (NCT01752634). This post hoc analysis assessed the ability of secukinumab to achieve Psoriatic Arthritis Disease Activity Score (PASDAS)-based remission or low disease activity (LDA) through 2 years among patients with PsA in the FUTURE 2 study. METHODS: PASDAS (cut-off scores: remission ≤ 1.9; LDA > 1.9 and < 3.2; Moderate Disease Activity ≥ 3.2 and < 5.4; and high disease activity [HDA] ≥ 5.4) was assessed in the overall population (tumour necrosis factor inhibitor [TNFi]-naïve and TNFi-experienced), in patients stratified by prior TNFi use and by disease duration at weeks 16, 52 and 104. The impact of secukinumab on individual PASDAS core components and on the relationship between PASDAS states and patient-reported outcomes (PROs), including physical function, health-related quality of life (HRQoL) and work productivity, were also assessed. Data for the approved doses of secukinumab (300 and 150 mg) are reported. PASDAS scores and core components were reported as observed, and PROs were analysed using mixed models for repeated measures. RESULTS: In the overall population, PASDAS remission and LDA were achieved in 15.6% and 22.9%, respectively, of patients treated with secukinumab 300 mg and in 15.2% and 19.2%, respectively, in the secukinumab 150 mg group versus 2.3% and 13.8%, respectively, with placebo at week 16. In the TNFi-naïve group, a higher proportion of patients achieved remission + LDA at week 16 with secukinumab 300 and 150 mg (46.2% and 42.9%, respectively) versus placebo (17.5%), with corresponding responses in TNFi-experienced patients being 22.6% and 19.4% versus 13.3%. Remission/LDA responses with secukinumab were sustained through 2 years. Patients achieving remission/LDA reported greater improvements in PROs than patients in HDA through 2 years. CONCLUSIONS: Secukinumab-treated patients achieved higher PASDAS-defined remissions or LDA compared with placebo at week 16, which were sustained through 2 years. Remission/LDA was achieved by both TNFi-naïve and TNFi-experienced patients treated with secukinumab, with higher rates in TNFi-naïve patients. Secukinumab-treated patients achieving remission/LDA reported significantly greater improvements in PROs, including physical function and different dimensions of health-related quality of life and work, than patients in HDA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01752634 . Registered on December 19, 2012. EUDRACT, 2012-004439-22 . Registered on December 12, 2012.

Development and validation of the Burnt Hand Outcome Tool (BHOT): A patient-led questionnaire for adults with hand burns.

Hand burns are unique in their functional, aesthetic and emotional impact on patients. Measuring the progress of a patient's ability to carry out essential and desired tasks, their emotional state, interaction with society as well as scar, pain and itch as their burn heals, has until now relied on the use of a combination of several different tools. We have developed a questionnaire specifically to address the multiple different aspects of the impact of a hand burn on a patient. This has been validated in a study of adult patients with hand burns in a UK unit, by a variety of psychometric tests. Ninety-four patients entered the study and questionnaires were completed over the course of a year at five time points. The total BHOT and DASH questionnaires completed at each time point was as follows: 86 before; 52 healed; 29 at 3 months; 31 at 6 months; 28 at 1 year, i.e. 226 DASH and 226 BHOT questionnaires in total. The questionnaire has been shown to have excellent reliability, criterion validity, construct validity, and responsiveness. The result is the Burnt Hand Outcome Tool (BHOT), a patient reported, quick and easy to use yet comprehensive questionnaire specifically for adult patients with burns to the hand.

The Hand Burn Severity (HABS) score: A simple tool for stratifying severity of hand burns.

Hand burns represent a unique challenge to the burns team due to the intricate structure and unrivalled functional importance of the hand. The initial assessment and prognosis relies on consideration of the specific site involved as well as depth of the burn. We created a simple severity score that could be used by referring non-specialists and researchers alike. The Hand Burn Severity (HABS) score stratifies hand burns according to severity with a numerical value of between 0 (no burn) and 18 (most severe) per hand. Three independent assessors scored the photographs of 121 burned hands of 106 adult and paediatric patients, demonstrating excellent inter-rater reliability (r=0.91, p<0.0001 on testing with Lin's correlation coefficient). A significant relationship was shown between the HABS score and a reliable binary outcome of the requirement for surgical excision on Mann-Whitney U testing (U=152; Z=9.8; p=0.0001). A receiver operator characteristic (ROC) curve analysis found a cut off score of 5.5, indicating that those with a HABS score below 6 did not require an operation, whereas those with a score above 6 did. The HABS score was shown to be more sensitive and specific that assessment of burn depth alone. The HABS score is a simple to use tool to stratify severity at initial presentation of hand burns which will be useful when referring, and when reporting outcomes.

Bilateral globus pallidus internus deep brain stimulation for dyskinetic cerebral palsy supports success of cochlear implantation in a 5-year old ex-24 week preterm twin with absent cerebellar hemispheres.

BACKGROUND: Early onset dystonia (dyskinesia) and deafness in childhood pose significant challenges for children and carers and are the cause of multiple disability. It is particularly tragic when the child cannot make use of early cochlear implantation (CI) technology to relieve deafness and improve language and communication, because severe cervical and truncal dystonia brushes off the magnetic amplifier behind the ears. Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) neuromodulation can reduce dyskinesia, thus supporting CI neuromodulation success. METHODS: We describe the importance of the order of dual neuromodulation surgery for dystonia and deafness. First with bilateral GPi DBS using a rechargeable ACTIVA-RC neurostimulator followed 5 months later by unilateral CI with a Harmony (BTE) Advanced Bionics Hi Res 90 K cochlear device. This double neuromodulation was performed in series in a 12.5 kg 5 year-old ex-24 week gestation-born twin without a cerebellum. RESULTS: Relief of dyskinesia enabled continuous use of the CI amplifier. Language understanding and communication improved. Dystonic storms abated. Tolerance of sitting increased with emergence of manual function. Status dystonicus ensued 10 days after ACTIVA-RC removal for infection-erosion at 3 years and 10 months. He required intensive care and DBS re-implantation 3 weeks later together with 8 months of hospital care. Today he is virtually back to the level of functioning before the DBS removal in 2012 and background medication continues to be slowly weaned. CONCLUSION: This case illustrates that early neuromodulation with DBS for dystonic cerebral palsy followed by CI for deafness is beneficial. Both should be considered early i.e. under the age of five years. The DBS should precede the CI to maximise dystonia reduction and thus benefits from CI. This requires close working between the paediatric DBS and CI services.

The microvascular anastomotic coupler for venous anastomoses in free flap breast reconstruction improves outcomes.

BACKGROUND: Venous couplers are ubiquitous around the world and are a useful tool for the reconstructive microsurgeon. A systematic review of coupler performance studies demonstrated a thrombosis rate range of 0% to 3%, whilst the average time of using the device is 5 minutes. There is sparse published data on cost analysis and the impact of operator experience on the anastomotic coupler device success. Improvements in outcomes other than time benefits have also not been shown. This study aims to address these deficiencies in the literature. METHODS: A retrospective clinical study was undertaken, aiming to compare equivalent groups of patients that had free flap surgery with venous micro-anastomoses with those that had sutured anastomoses. The cohort comprised all patients undergoing microsurgical breast reconstruction at the St Andrew's Centre for Plastic Surgery & Burns from January 2009 to December 2014. RESULTS: Between January 2010 to December 2014, 1,064 patients underwent 1,206 free flap breast reconstructions. The average age of patients was 50 years. Seventy percent of patients underwent mastectomy and immediate reconstruction during this period with the remaining 30% having a delayed reconstruction. The 1,206 free flaps comprised of 83 transverse myocutaneous gracilis (TMG) flaps, and 1,123 deep inferior epigastric artery perforator (DIEP) flaps. In total the coupler was used in 319 flaps, 26% of the cohort. There was a statistically significant clinical benefit in using the anastomotic coupler for venous anastomosis. Overall, the return to theatre rate was 12.69% whilst the overall flap loss rate was 0.75%. The overall coupler failure rate was significantly less at 1.4% whilst sutured vein failure rate was 3.57% (P=0.001). CONCLUSIONS: The anastomotic coupler for venous anastomosis in free flap surgery is associated with reduced operating times, reduced take-backs to theatre and cost benefits. This is the first study to demonstrate clear clinical benefits to anastomotic couplers, and suggests that these may be the gold standard for venous microanastomosis. With increasing experience with their use and technological advances, these outcomes may continue to improve.

Preoperative computed tomography angiography for planning DIEP flap breast reconstruction reduces operative time and overall complications.

BACKGROUND: The approach and operative techniques associated with breast reconstruction have steadily been refined since its inception, with abdominal perforator-based flaps becoming the gold standard reconstructive option for women undergoing breast cancer surgery. The current study comprises a cohort of 632 patients, in whom specific operative times are recorded by a blinded observer, and aims to address the potential benefits seen with the use of computer tomography (CT) scanning preoperatively on operative outcomes, complications and surgical times. METHODS: A prospectively recorded, retrospective review was undertaken of patients undergoing autologous breast reconstruction with a DIEP flap at the St Andrews Centre over a 4-year period from 2010 to 2014. Computed tomography angiography (CTA) scanning of patients began in September 2012 and thus 2 time periods were compared: 2 years prior to the use of CTA scans and 2 years afterwards. For all patients, key variables were collected including patient demographics, operative times, flap harvest time, pedicle length, surgeon experience and complications. RESULTS: In group 1, comprising patients within the period prior to CTA scans, 265 patients underwent 312 flaps; whilst in group 2, the immediately following 2 years, 275 patients had 320 flaps. The use of preoperative CTA scans demonstrated a significant reduction in flap harvest time of 13 minutes (P<0.013). This significant time saving was seen in all flap modifications: unilateral, bilateral and bipedicled DIEP flaps. The greatest time saving was seen in bipedicle flaps, with a 35-minute time saving. The return to theatre rate significantly dropped from 11.2% to 6.9% following the use of CTA scans, but there was no difference in the total failure rate. CONCLUSIONS: The study has demonstrated both a benefit to flap harvest time as well as overall operative times when using preoperative CTA. The use of CTA was associated with a significant reduction in complications requiring a return to theatre in the immediate postoperative period. Modern scanners and techniques can reduce the level of ionising radiation, facilitating patients being able to benefit from the advantages that this preoperative planning can convey.

Stacked and bipedicled abdominal free flaps for breast reconstruction: considerations for shaping.

BACKGROUND: Stacked and bipedicled abdominal flaps are useful in women who require a large breast reconstruction but have relative paucity of abdominal tissue. A new classification system is described to assist the surgeon in achieving the best possible aesthetic outcome. METHODS: A retrospective review of 25 consecutive stacked and/or bipedicled deep inferior epigastric perforator (DIEP) flap reconstructions was assessed from 2009 to 2014. Demographic data and key variables were prospectively collected in our breast reconstruction database and an aesthetic classification devised. There are four main subtypes, (I) folded; (II) divided; (III) coned; and (IV) divided and folded. Each of these subtypes can be moulded in a symmetrically or asymmetrically fashion depending on the contralateral breast shape together with distribution and consistency of fat within the abdominal flap. RESULTS: Of the 25 patients, three-quarter were immediate reconstruction, with an average age of 48 years and a median follow-up of 2 years 10 months. Just over half the patients (57%) had bipedicle flaps with two recipient donor vessels with the remaining 43% had stacked flaps. The most common recipient sites are the thoracodorsal vessels (62%) and intercostal perforators (26%). The average abdominal pannus weight was 610 grams (SD: 320 grams), with a hemi-abdominal weight of 305 grams. Two patients had haematomas, of which one lost their reconstruction. Another patient had a venous congestion flap which was salvaged. CONCLUSIONS: Bipedicled or stacked abdominal flaps allow the all four zones of the abdominal tissue to be used in unilateral breast reconstruction. The approach of tailoring the abdominal flaps to match the contralateral breast reconstruction is largely an art form. The paper aims to bring some meaningful system to aid the surgeon to achieve the best possible outcome with the components presented to them.

Replantation of digits: a review of predictive factors for survival.

UNLABELLED: The survival of 75 consecutive digital replantations carried out between 2006 and 2010 at a regional hand centre in the United Kingdom was determined. The patient demographics, mechanism of injury, co-morbid factors, operative and post-operative details were extracted and reviewed from the medical and hand therapy notes. Predictive factors of survival were determined by using univariate and multivariate statistical analysis. The survival rate was 70%. Arterial thrombosis was the leading cause of replant failure, followed by venous congestion. Smoking, level of amputation, number of nerves repaired, warm ischaemia time and timing of replantation were independent predictors of replant survival. However, only warm ischaemia time less than 6 hours and 30 minutes and replantations done within 'office hours' showed significance on multivariate logistic regression. Our study suggests that replantations done in daylight hours, when feasible, with rested staff and a full complement of the theatre team are likely to have better outcomes. LEVEL OF EVIDENCE: Level IV case series.

European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update.

BACKGROUND: Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. METHODS: A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. RESULTS: The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. CONCLUSIONS: These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.

Effect of certolizumab pegol over 96†weeks in patients with psoriatic arthritis with and without prior antitumour necrosis factor exposure.

OBJECTIVE: Previous reports of RAPID-PsA (NCT01087788) demonstrated efficacy and safety of certolizumab pegol (CZP) over 24 weeks in patients with psoriatic arthritis (PsA), including patients with prior antitumour necrosis factor (TNF) therapy. We report efficacy and safety data from a 96-week data cut of RAPID-PsA. METHODS: RAPID-PsA was placebo-controlled to week 24, dose-blind to week 48 and open-label to week 216. We present efficacy data including American College of Rheumatology (ACR)/Psoriasis Area and Severity Index (PASI) responses, HAQ-DI, pain, minimal disease activity (MDA), modified total Sharp score (mTSS) and ACR responses in patients with/without prior anti-TNF exposure, in addition to safety data. RESULTS: Of 409 patients randomised, 273 received CZP from week 0. 54 (19.8%) CZP patients had prior anti-TNF exposure. Of patients randomised to CZP, 91% completed week 24, 87% week 48 and 80% week 96. ACR responses were maintained to week 96: 60% of patients achieved ACR20 at week 24, and 64% at week 96. Improvements were observed with both CZP dose regimens. ACR20 responses were similar in patients with (week 24: 59%; week 96: 63%) and without (week 24: 60%; week 96: 64%) prior anti-TNF exposure. Placebo patients switching to CZP displayed rapid clinical improvements, maintained to week 96. In patients with ≥3% baseline skin involvement (60.8% week 0 CZP patients), PASI responses were maintained to week 96. No progression of structural damage was observed over the 96-week period. In the Safety Set (n=393), adverse events occurred in 345 patients (87.8%) and serious adverse events in 67 (17.0%), including 6 fatal events. CONCLUSIONS: CZP efficacy was maintained to week 96 with both dose regimens and in patients with/without prior anti-TNF exposure. The safety profile was in line with that previously reported from RAPID-PsA, with no new safety signals observed with increased exposure. TRIAL REGISTRATION NUMBER: NCT01087788.