Search

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis and extreme lethality. The backbone of SCLC treatment over the past several decades has been platinum-based doublet chemotherapy, with the recent addition of immunotherapy providing modest benefits in a subset of patients. However, nearly all patients treated with systemic therapy quickly develop resistant disease, and there is an absence of effective therapies for recurrent and progressive disease. Here we conducted CRISPR-Cas9 screens using a druggable genome library in multiple SCLC cell lines representing distinct molecular subtypes. This screen nominated exportin-1, encoded by XPO1, as a therapeutic target. XPO1 was highly and ubiquitously expressed in SCLC relative to other lung cancer histologies and other tumor types. XPO1 knockout enhanced chemosensitivity, and exportin-1 inhibition demonstrated synergy with both first- and second-line chemotherapy. The small molecule exportin-1 inhibitor selinexor in combination with cisplatin or irinotecan dramatically inhibited tumor growth in chemonaïve and chemorelapsed SCLC patient-derived xenografts, respectively. Together these data identify exportin-1 as a promising therapeutic target in SCLC, with the potential to markedly augment the efficacy of cytotoxic agents commonly used in treating this disease. Significance: CRISPR-Cas9 screening nominates exportin-1 as a therapeutic target in SCLC, and exportin-1 inhibition enhances chemotherapy efficacy in patient-derived xenografts, providing a novel therapeutic opportunity in this disease.

Lineage plasticity is implicated in treatment resistance in multiple cancers. In lung adenocarcinomas (LUAD) amenable to targeted therapy, transformation to small cell lung cancer (SCLC) is a recognized resistance mechanism. Defining molecular mechanisms of neuroendocrine (NE) transformation in lung cancer has been limited by a paucity of pre/posttransformation clinical samples. Detailed genomic, epigenomic, transcriptomic, and protein characterization of combined LUAD/SCLC tumors, as well as pre/posttransformation samples, supports that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm. We observed enhanced expression of genes involved in the PRC2 complex and PI3K/AKT and NOTCH pathways. Pharmacologic inhibition of the PI3K/AKT pathway delayed tumor growth and NE transformation in an EGFR-mutant patient-derived xenograft model. Our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer. Significance: The difficulty in collection of transformation samples has precluded the performance of molecular analyses, and thus little is known about the lineage plasticity mechanisms leading to LUAD-to-SCLC transformation. Here, we describe biological pathways dysregulated upon transformation and identify potential predictors and potential therapeutic vulnerabilities of NE transformation in the lung. See related commentary by Meador and Lovly, p. 2962. This article is highlighted in the In This Issue feature, p. 2945

Only a subset of cancer patients responds to checkpoint blockade inhibition in the clinic. Strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) has shown efficacy in preclinical models, but GITR engagement is ineffective in controlling advanced, poorly immunogenic tumors, such as B16 melanoma, and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) depletes regulatory T cells (Tregs), expands tumor-specific effector T cells (Teffs) via homeostatic proliferation, and induces immunogenic cell death. GITR agonism has an inhibitory effect on Tregs and activates Teffs. We therefore hypothesized that CTX and GITR agonism would promote effective antitumor immunity. Here we show that the combination of CTX and GITR agonism controlled tumor growth in clinically relevant mouse models. Mechanistically, we show that the combination therapy caused tumor cell death, clonal expansion of highly active CD8+ T cells, and depletion of Tregs by activation-induced cell death. Control of tumor growth was associated with the presence of an expanded population of highly activated, tumor-infiltrating, oligoclonal CD8+ T cells that led to a diminished TCR repertoire. Our studies show that the combination of CTX and GITR agonism is a rational chemoimmunotherapeutic approach that warrants further clinical investigation.

Background Lineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transformation in the context of acquired resistance to targeted inhibition of driver mutations. LUAD-to-LUSC transdifferentiation, occurring in up to 9% of EGFR-mutant patients relapsed on osimertinib, is associated with notably poor prognosis. We hypothesized that multi-parameter profiling of the components of mixed histology (LUAD/LUSC) tumors could provide insight into factors licensing lineage plasticity between these histologies. Methods We performed genomic, epigenomics, transcriptomics and protein analyses of microdissected LUAD and LUSC components from mixed histology tumors, pre-/post-transformation tumors and reference non-transformed LUAD and LUSC samples. We validated our findings through genetic manipulation of preclinical models in vitro and in vivo and performed patient-derived xenograft (PDX) treatments to validate potential therapeutic targets in a LUAD PDX model acquiring LUSC features after osimertinib treatment. Results Our data suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events. We observed consistent relative upregulation of PI3K/AKT, MYC and PRC2 pathway genes. Concurrent activation of PI3K/AKT and MYC induced squamous features in EGFR-mutant LUAD preclinical models. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous-features in an EGFR-mutant patient-derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re-sensitized resistant squamous-like tumors to osimertinib. Conclusions Our findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and potential therapeutic targets to constrain or prevent lineage plasticity.

Summary Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation.

Although cancer immunotherapy with PD-(L)1 blockade is now routine treatment for patients with lung cancer, remarkably little is known about acquired resistance. We examined 1,201 patients with NSCLC treated with PD-(L)1 blockade to clinically characterize acquired resistance, finding it to be common (occurring in more than 60% of initial responders), with persistent but diminishing risk over time, and with distinct metastatic and survival patterns compared to primary resistance. To examine the molecular phenotype and potential mechanisms of acquired resistance, we performed whole transcriptome and exome tumor profiling in a subset of NSCLC patients (n=29) with acquired resistance. Systematic immunogenomic analysis revealed that tumors with acquired resistance generally had enriched signals of inflammation (including IFNγ signaling and inferred CD8+ T cells) and could be separated into IFNγ upregulated and stable subsets. IFNγ upregulated tumors had putative routes of resistance with signatures of dysfunctional interferon signaling and mutations in antigen presentation genes. Transcriptomic profiling of cancer cells from a murine model of acquired resistance to PD-(L)1 blockade also showed evidence of dysfunctional interferon signaling and acquired insensitivity to in vitro interferon gamma treatment. In summary, we characterized clinical and molecular features of acquired resistance to PD-(L)1 blockade in NSCLC and found evidence of ongoing but dysfunctional IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance.

BACKGROUND The Leila Rose Foundation ("the Foundation") was established in April 2011, to address financial toxicity as well as the gaps in knowledge and support for families affected by a rare childhood cancer diagnosis in Australia. AIM The aim of this brief report is to analyze the diagnostic trends surrounding the rare cancer diagnoses for patients referred to the Foundation over the past decade and to present case studies evaluating the role of the Foundation's Family Support Coordinator in providing tailored, individualized support for families. METHODS Eligibility for family support is restricted to children ≤ 14 years of age at diagnosis with a cancer that has an incidence less than 5% of all childhood cancers in Australia as reflected by national registry data. The analysis of diagnostic trends in this report, was based upon a systematic review of enrolment records. The role of the Family Support Coordinator is presented in four different case studies. RESULTS As at 1 November 2020, the Foundation has supported 197 families affected by rare childhood cancer. Financial support of $825,000 has been provided directly to these families. Enrollment records demonstrate that 35 patients representing 18% of all enrollments have had a unique diagnosis that has not been recorded for any other enrolled patient highlighting that these diagnoses are very rare. The most frequent diagnoses have included Medulloblastoma, Ewing's Sarcoma and Wilm's Tumor (20, 19, 19 patients respectively). The Family Support Coordinator role has provided individualized support for families which has been greatly appreciated based upon ad hoc family feedback. CONCLUSIONS Challenges remain in terms of improving outcomes for families affected by rare childhood cancer. The Foundation is committed to leaving no stone unturned and delivering its unique support services to families in order to reduce the burden caused by a rare childhood cancer diagnosis both now and in the future.

Purpose of review To describe the key features and epidemiology of traumatic brain injury (TBI) and how they may be changing, with an emphasis on how this may affect care in the intensive care unit. Recent findings TBI has been traditionally perceived as occurring mainly in a younger, predominantly male population injured in high velocity motor vehicle crashes or assaults. However, there are an increasing number of patients over 65 years who have sustained a TBI secondary to low velocity falls. Considering the effects of frailty, comorbidities and extracranial injuries is important when making management decisions. Mild TBI comprises a third of those admitted and as a significant proportion may have poor outcomes secondary to their TBI they should be assessed to ensure appropriate follow-up. Multimodal monitoring may offer a way in the future to offer more personalised management to this very complex and heterogeneous patient group. Summary This review highlights the urgent need to develop more age-inclusive TBI consensus management guidelines aimed at improving short- and long-term outcomes for the large and growing TBI population. Being elderly does not necessarily portend a poor outcome, and more research is needed to better triage, guide management and prognosticate on these patients.

Lineage plasticity, a capacity to reprogram cell phenotypic identity under evolutionary pressure, is implicated in treatment resistance and metastasis in multiple cancers. In lung adenocarcinomas (LUADs) amenable to treatment with targeted inhibitors, transformation to an aggressive neuroendocrine (NE) carcinoma resembling small cell lung cancer (SCLC) is a recognized mechanism of acquired resistance. Defining molecular mechanisms of NE transformation in lung cancer has been limited by a paucity of well annotated pre- and post-transformation clinical samples. We hypothesized that mixed histology LUAD/SCLC tumors may capture cancer cells proximal to, and on either side of, histologic transformation. We performed detailed genomic, epigenomic, transcriptomic and proteomic characterization of combined LUAD/SCLC tumors as well as pre- and post-transformation clinical samples. Our data support that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm in pre-transformation LUADs. Consistent shifts in gene expression programs in NE transformation include induction of several stem/progenitor cell regulatory pathways, including upregulation of PRC2 and WNT signaling, and suppression of Notch pathway activity. We observe induction of PI3K/AKT and an immunosuppressive phenotype in NE transformation. Taken together our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer.

Retinopathy of prematurity (ROP), previously known as retrolental fibroplasia, was first described by Terry in 1942 (1). It is a vasoproliferative disorder that is a leading cause of childhood blindness in the United States, causing 550 new cases of infant blindness each year (2). It occurs principally in premature infants treated with high concentrations of oxygen. There are two phases of ROP: (i) an acute phase in which normal vasculogenesis is interrupted, and (ii) a chronic phase in which vascular membranes proliferate into thevitreous. This proliferation can lead to retinal detachment, scarring of the macula, and significant visual loss (3).This article summarizes the incidence, pathophysiology, and classification of ROP. Current protocols for evaluating and treating ROP, as well as long-term sequelae, are also described.

Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively), which are associated with distinct therapeutic vulnerabilities. To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 54,523 cellular transcriptomes from 21 human biospecimens. Our single-cell SCLC atlas reveals tumor diversity exceeding lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discovered a PLCG2-high tumor cell population with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival, and manipulation of PLCG2 expression in cells confirms correlation with key metastatic markers. Treatment and subtype are associated with substantial phenotypic changes in the SCLC immune microenvironment, with greater T-cell dysfunction in SCLC-N than SCLC-A. Moreover, the recurrent, PLCG2-high subclone is associated with exhausted CD8+ T-cells and a pro-fibrotic, immunosuppressive monocyte/macrophage population, suggesting possible tumor-immune coordination to promote metastasis.

Background Long-term clinical registries are essential tools to evaluate new therapies in a patient population that differs from those in randomized clinical trials. The objectives are to describe the profile of rheumatoid arthritis (RA) patients treated with anti-TNF agents in Canadian routine care. Methods RA patients eligible for treatment with Infliximab (IFX), golimumab (GLM) or intravenous golimumab (GLM-IV) as per their respective Canadian product monographs were enrolled into the BioTRAC registry between 2002 and 2017. Study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed by changes in disease activity. Safety was evaluated by the incidence of adverse events (AEs) and drug survival. Results Of the 890 IFX-, 530 GLM- and 157 GLM-IV-treated patients, the proportion of females ranged from 77.0–86.6%, the mean ages from 55.8–57.7 and the mean disease duration from 6.5–8.6 years. A significant decrease in baseline disease duration and disease activity parameters (DAS, TJC, SJC, HAQ, AM stiffness, MDGA, PtGA, CRP, ESR) was observed over time. Treatment with IFX, GLM- and GLM-IV significantly improved all disease parameters over time. The incidence of AEs was 105, 113 and 82.6 /100 PYs and the incidence of SAEs was 11.7, 11.2 and 4.68 /100 PYs for IFX, GLM- and GLM-IV-treated patients, respectively. Conclusion Differences in baseline characteristics between patients treated with an anti-TNFs over time shows the evolution of treatment modalities over time. All treatments significantly reduced disease activity and improved functionality in a similar fashion. The incidence of adverse events was consistent with the safety profiles of IFX and GLM. Trial registration ClinicalTrials.gov Identifier: NCT00741793 (Retrospectively registered on August 26, 2008).

Background Long-term registries are essential to evaluate new therapies in a patient population that differs from clinical trials and usually varies over time. Objectives To describe the profile of psoriatic arthritis (PsA) patients selected for treatment with infliximab (IFX), golimumab (GLM) or ustekinumab (UST) treatment in Canadian routine care and to describe the long-term real-world effectiveness and safety of these agents. Methods 462 PsA patients treated with IFX, GLM or UST were enrolled into the Biologic Treatment Registry Across Canada (BioTRAC) registry between 2006-2015, 2010-2017 and 2014-2017, respectively. Study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed with changes in TJC28, SJC28, skin, enthesitis, dactylitis, pain, HAQ, acute phase reactants. Safety was evaluated with the incidence of adverse events (AEs) and drug survival rates. Results Of the 111 IFX-, 281 GLM- and 70 UST-treated patients, the proportion of males were 52.3%, 46.3% and 37.1%, the mean age was 48.4, 52.8 and 53.1 years and the mean disease duration was 5.8, 6.1 and 5.7 years, respectively. Most patients were bio-naive (85.6%, 77.9% and 55.7% for IFX, GLM and UST, respectively (p Treatment with IFX, GLM and UST was associated with significant improvements in all disease parameters over time (P AEs were reported for 74.8%, 69.8% and 52.9% (138, 114 and 115 events/100 PYs) and SAEs for 19.8%, 8.5% and 5.7% (8.8, 19.6 and 28.6 events/100 PYs) covering 325, 567 and 87 years of exposure for IFX-, GLM- and UST-treated patients, respectively. One, one and no death occurred IFX-, GLM- and UST-treated patients, respectively. The proportion of patients who discontinued treatment were 63.1%, 50.9% and 50.0% over a mean exposure of 2.9, 1.9 and 1.2 years to IFX, GLM and UST, respectively. Conclusion Differences in baseline characteristics between patients treated with an anti-TNF over an anti-IL12/23 agent suggest that the level of joint to skin involvement might be driving physician choice when the time comes to choose a biologic agent. IFX, GLM and UST treatment significantly reduced disease activity and improved functionality in a similar fashion and were well tolerated in patients with PsA. Disclosure of Interests Proton Rahman: None declared, Regan Arendse Grant/research support from: Janssen Sponsored Study, Isabelle Fortin Grant/research support from: ABBVIE, AMGEN, ASTRAZENECA, BMS, CELGENE, GSK, JANSSEN, PFIZER, SANOFI, UCB, Consultant for: LILLY, NOVARTIS, SANOFI, Speakers bureau: NOVARTIS, PFIZER, Andrew Chow Grant/research support from: Abbvie, Celgene, EliLilly, GSK, Janssen, Novartis, Pfizer, UCB, Consultant for: Abbvie, BMS, Celgene, EliLilly, GSK, Janssen, Novartis, Pfizer, Roche,UCB, Speakers bureau: Abbvie, BMS, EliLilly, Janssen, Novartis, Pfizer, Majed Khraishi Grant/research support from: Novartis, Consultant for: Amgen, Celgene, Gebro, Janssen, Novartis, Pfizer, Lilly, Merck, Suneil Kapur Grant/research support from: Abbvie, Merck, Janssen, Novartis, Eli Lilly, Amgen, Michel Zummer: None declared, Jon Chan Grant/research support from: Janssen, UCB, Novartis, Pfizer, Celgene, Consultant for: Amgen, Celgene, Eli Lilly, Janssen, Amgen, Abbvie, Novartis, Pfizer, UCB, Sandoz, Merck, Larissa Lisnevskaia Grant/research support from: Janssen Sponsored Study, Raheem Kherani Grant/research support from: Janssen, BMS, Abbvie, Consultant for: Abbvie, Amgen, BMS, Janssen, Lilly, Merck, Pfizer, Roche, Speakers bureau: Jannsen, BMS, Emmanouil Rampakakis : None declared, Odalis Asin MIilan Employee of: Employee of Janssen, Allen Lehman Employee of: Employee of Janssen, Meagan Rachich Shareholder of: Janssen, Employee of: Employee of Janssen, Francois Nantel Shareholder of: Janssen, Employee of: Employee of Janssen

Background Treatment selection in routine clinical care is driven by treatment guidelines, physician judgment, patient preferences, and regional reimbursement policies, which may vary over time and among geographic regions. Objectives The objective of this analysis is to investigate the regional and temporal variability of the profile of anti-TNF naive psoriatic arthritis (PsA) patients at initiation of adalimumab (ADA) treatment following failure of initial non-biologic treatment. Methods COMPLETE-PsA is an ongoing Canadian observational study of anti-TNFα naive adults with active PsA who require change in their current treatment as per the judgement of their treating physician. Patients are followed for up to 2 years. Regional variation was assessed for the following regions: British Columbia/Manitoba (BC/MB), Newfoundland/Nova Scotia (NL/NS), ontario (ON), and Quebec (QC). Temporal variation was assessed for the following periods: 2012-2014 and 2015-2017. Multivariate linear regression was used to evaluate the independent impact of region and time period on disease activity (DAS28) and patient function (HAQ). Results A total of 278 patients were included, of whom 68 (24.5%) were from BC/MB, 25 (9%) from NL/NS, 104 (37.4%) from on, and 81 (29.1%) from QC. One hundred fifty-three patients (55%) were enrolled in 2012-2014 and 125 (45%) in 2015-2017. Using univariate analysis, significant regional variation at aDA initiation was observed for the following disease parameters: BSA Conclusion The results of this analysis demonstrate that there is significant regional and temporal variation in the profile of PsA patients initiated on aDA treatment in Canadian routine care. The impact of this profile variation on treatment outcomes requires further investigation. Acknowledgement The authors wish to acknowledge JSS Medical Research, Montreal (QC) Canada for statistical analysis, medical writing and editorial assistance during the preparation of this abstract, and Nathalie Ross, PhD, for editorial assistance. AbbVie provided funding to JSS Medical Research and Nathalie Ross for this work. Disclosure of interests Majed Khraishi Consultant for: abbVie, Speakers bureau: abbVie, Louis Bessette Grant/research support from: amgen, BMS, Janssen, Roche, UCB, abbVie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Consultant for: amgen, BMS, Janssen, Roche, UCB, abbVie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Speakers bureau: amgen, BMS, Janssen, Roche, UCB, abbVie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Samuel Silverberg Consultant for: abbVie, Janssen, Boulos Haraoui Consultant for: abbVie, amgen, Eli Lilly, Merck, Pfizer, Sandoz, UCB, BMS, Janssen, Pfizer, Speakers bureau: amgen, Pfizer, and UCB, andrew Chow Consultant for: abbVie, amgen, BMS, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Speakers bureau: abbVie, BMS, Janssen, Pfizer, Takeda, Yatish Setty Consultant for: abbVie, Valencia P. Remple Shareholder of: abbVie, Employee of: abbVie

8509 Background: Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively), which are associated with distinct therapeutic vulnerabilities. The emerging consensus on SCLC subtypes has led to new questions, such as whether subtypes are associated with different disease stages, metastatic potential, or immune microenvironments; whether there is plasticity between subtypes; and whether novel SCLC phenotypes exist. Single cell RNA sequencing (scRNA-seq) offers a unique opportunity to address these questions by dissecting intratumoral transcriptional heterogeneity and the surrounding tumor microenvironment (TME). However, efforts to apply this technology to human SCLC tumors have been limited, as these tumors are infrequently resected. Methods: We have optimized protocols to process both surgical resections and biopsies to construct the first single-cell atlas of SCLC patient tumors (N = 21), with comparative lung adenocarcinoma (LUAD) and normal lung data. We leverage computational methods including diffusion maps and non-negative matrix factorization to perform a deep annotation of SCLC phenotypes and the surrounding immune TME. We perform validation experiments using flow cytometry, Vectra, and immunohistochemistry in independent SCLC cohorts, as well as genetic manipulation in preclinical SCLC models. Results: Our data reveals substantial transcriptional heterogeneity in SCLC both within and across tumors and confirms a pro-metastatic gene program in SCLC-N subtype characterized by epithelial-mesenchymal transformation and axonogenesis. Beyond known subtypes, we discover a PLCG2-high tumor cell population with stem-like, pro-metastatic features that recurs across subtypes and predicts significantly worse overall survival. Manipulation of PLCG2 expression in cells confirms correlation with key metastatic markers. Treatment and subtype are associated with substantial phenotypic changes in the SCLC immune microenvironment, with greater T-cell dysfunction in SCLC-N than SCLC-A. Moreover, the recurrent, PLCG2-high subclone is associated with exhausted CD8+ T-cells and a pro-fibrotic, immunosuppressive monocyte/macrophage population, suggesting possible tumor-immune coordination to promote metastasis. Conclusions: This atlas of SCLC illustrates how canonical subtypes and a novel PLCG2-high recurrent tumor subclone enlist diverse gene programs to create tumor heterogeneity and facilitate metastasis in a profoundly immunosuppressed TME. Our dataset provides further insight into tumor and immune biology in SCLC at single-cell resolution, with potential implications for design of novel targeted therapies and immunotherapeutic approaches.

Background:COMPLETE-AS was an observational study among Canadian biologic-naïve adults with active ankylosing spondylitis (AS) treated with either adalimumab or subsequent non-biologic disease-modifying anti-rheumatic drugs and/or non-steroidal anti-inflammatory drugs (nbDMARD/NSAID) after having switched from initial treatment with a preceding nbDMARD and/or NSAID due to lack of response or intolerance, as per treating physician judgement.Objectives:To assess the impact of adalimumab on disease activity and patient-reported outcomes among adalimumab- vs. nbDMARD/NSAID-treated patients over 24 months.Methods:Patients were enrolled between July 2011 and December 2017 and followed for up to 24 months. Treatment was per routine care and all analyses were perfomed using the intent-to-treat (ITT) approach. Between-group differences for change in patient-reported disease activity (BASDAI), morning stiffness (minutes/day), functional limitation (BASFI), quality of life (QoL: SF-12), depression (BDI-II), and work productivity (WLQ) were assessed with repeated measures models for overall treatment effect; baseline-adjusted estimates (least square means [LSM]) for each visit were produced. Achievement of, and time to the following endpoints were assessed: 50% improvement from baseline in BASDAI (BASDAI50); minimum clinically important improvements (MCIIs) in BASDAI (Δ≥1.1); BASFI (Δ≥0.6); SF-12 physical component score (PCS; Δ≥4.4) and mental component score (MCS; Δ≥3.1); and low disease activity for BASDAI (Results:A total of 452 adalimumab-treated patients and 187 nbDMARD/NSAID-treated patients were enrolled in the study and included in the analyses. At baseline, mean (SD) BASDAI [6.4 (1.8) vs. 5.0 (1.8); pOver 24 months, adalimumab-treated patients had significantly lower overall BASDAI scores compared to nbDMARD/NSAID-treated patients [estimate (95% CI): -0.7 (-1.2, -0.3); p=0.007]. BASFI scores were also significantly lower among adalimumab-treated patients over the course of the study [estimate (95% CI): -0.4 (-0.8, 0.0); p=0.013]. Both groups had statistically comparable outcomes for morning stiffness, BDI-II, WLQ, and SF-12.Adalimumab-treated patients were also at significantly higher odds of achieving therapeutic response thresholds, including BASDAI50 [OR (95% CI): 1.7 (1.2-2.3)], BASDAIAt month 24, baseline-adjusted BASDAI and BASFI was comparable (p>0.05): LSM (95%CI) 3.5 (3.3, 3.8) vs. 3.6 (3.2-4.0), and 2.9 (2.6-3.1) vs. 3.3 (2.9-3.7), respectively, for adalimumab-treated vs. nbDMARD/NSAID-treated patients.Conclusion:Among Canadian patients with active AS, adalimumab-treated patients reported a greater overall reduction in disease burden related to both self-reported disease activity and functional capacity compared to nbDMARD/NSAID-treated patients, along with higher odds and shorter time to achieving therapeutic response thresholds. Despite the overall beneficial effects observed with adalimumab, residual disease burden, however, is observed for Canadian AS patients even after 24 months of treatment.Acknowledgements:The authors wish to acknowledge JSS Medical Research for their contribution to the statistical analysis, medical writing, and editorial support during the preparation of this abstract. AbbVie provided funding to JSS Medical Research for this work.Disclosure of Interests:Louis Bessette Speakers bureau: Speaker for Amgen, BMS, Janssen, UCB, AbbVie, Pfizer, Merck, Celgene, Lilly, Novartis, Gilead, Sandoz, Fresenius Kabi, Consultant of: Consultant for Amgen, BMS, Janssen, UCB, AbbVie, Pfizer, Celgene, Lilly, Novartis, Gilead, Sandoz, Samsung Bioepis, Fresenius Kabi, Grant/research support from: Investigator for Amgen, BMS, Janssen, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Gilead, Andrew Chow Speakers bureau: Speaker for AbbVie, BMS, Janssen, Pfizer, Consultant of: Consultant for AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Grant/research support from: Investigator for AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Viktoria Pavlova Speakers bureau: Speaker for Amgen, Abbvie, BMS, Jenssen, Lilly, Merk, Novartis, Roche, UCB, and Pfizer, Consultant of: Consultant for Amgen, Abbvie, BMS, Jenssen, Lilly, Merk, Novartis, Roche, UCB, and Pfizer, Grant/research support from: Investigator for Janssen, UCB, Abbvie, and Pfizer; and received research grants from UCB, Marie-Claude Laliberté Employee of: Employee of AbbVie, Majed Khraishi Speakers bureau: Speaker for AbbVie, Consultant of: Consultant for AbbVie, Grant/research support from: Principal Investigator for AbbVie

Background: The aim of this study was to assess the real-world effectiveness and safety of certolizumab pegol (CZP) in rheumatoid arthritis (RA) patients, and the impact on patients’ productivity, pain, and fatigue, in Canadian practice. Methods: FαsT-CAN, a 2-year prospective, observational study, evaluated CZP use in Canadian adults with moderate to severe, active RA. The primary objective was to assess the proportion of patients achieving 28-joint Disease Activity Scores (DAS28) Results: The full analysis set (baseline DAS28 ⩾ 2.6, ⩾1 dose of CZP and ⩾1 valid post-baseline DAS28 measurement) included 451 of the 546 patients recruited into the study; a total of 229/451 (50.8%) patients completed Week 104. At Week 104, 90/451 (20.0%) patients achieved DAS28 < 2.6. Rapid improvements in disease activity, pain, and fatigue were observed. At Week 104, 66.2% of patients achieved HAQ-DI MCID. Patients employed at Week 104, reported reduced absenteeism, and improved productivity. CZP-related TEAEs were consistent with the known CZP safety profile. Conclusions: CZP was an effective RA treatment in Canadian practice, and no new CZP-related safety signals were identified. The improvements in household and workplace productivity are the first observations in a real-world Canadian setting.

Background To date, observational studies comparing the effectiveness of adalimumab (ADA) to non-biologic DMARDs (nbDMARD) in psoriatic arthritis (PsA) patients failing prior treatment are scarce. COMPLETE-PSA is a Canadian post-marketing observational study which assessed real-life effectiveness of ADA and non-biological therapies (NSAIDs and DMARDs) in PsA management following initial treatment failure. Objectives This analysis aimed to describe the baseline demographic and disease parameters of patients initiating nbDMARD or ADA and compare the 12 month real-life effectiveness of both treatments. Methods Patients eligible for COMPLETE PsA are anti-TNFα naive adults, with active PsA who require change in their treatment regimen, per the judgment of the treating physician. In the current analysis patients enrolled during Jul/2011–Jun/2016 were included. Outcome measures analysed were: DAS28, SF-12, DLQI, presence of extra-articular manifestations (EAMs; enthesitis and dactylitis), psoriasis BSA, achievement of modified MDA (defined as achievement of [i] 4 of 6 (MDA 1) and [ii] 5 of the following 6 criteria (MDA 2): TJC ≤1, SJC ≤1, BSA ≤3%, pain VAS≤15 mm, PtGA ≤20 and HAQ ≤0.5), modified remission (defined as SJC=0, TJC=0, absence of enthesitis and dactylitis, BSA ≤3% and HAQ ≤0.5), DAPSA LDA (≤14), and DAPSA remission (REM;≤4). Analyses were conducted by initial group assignment (intent-to-treat approach). Results 406 patients were included (nbDMARD n=146, ADA n=260). Baseline demographics were comparable between treatment groups. However, patients initiating ADA were more likely to be unemployed (47.3% ADA vs 34.9% nbDMARD, p=0.015), had higher DAS28 (4.8 vs 4.4, p=0.002) and total DLQI score (6.1 vs 4.3, p=0.007), and were more likely to have BSA ≥3% (44.6% vs 35.0%, p=0.063) and high DAPSA disease activity (50.8% vs 32.3%, p=0.015). A higher proportion of nbDMARD patients had dactylitis (36.1% vs 25.3%, p=0.023). No differences were observed between groups in enthesitis, overall EAMs, or QoL at baseline. Upon 12 months of treatment, mean adjusted DAS28 (2.6 vs 3.4, p Over time, 9.6% of ADA patients initiated another biologic and 32.2% of patients in the nbDMARD group initiated biologic treatment (p Conclusions PsA patients initiating ADA in Canadian routine clinical care have significantly greater baseline disease severity compared with those initiating nbDMARDs. However, 12 month ADA treatment improved disease control and EAMs. DAPSA-REM evaluation seems more sensitive than mMDA in differentiating both populations. Acknowledgements JSS Medical Research, Montreal, Canada Disclosure of Interest M. Khraishi Consultant for: AbbVie, Speakers bureau: AbbVie, L. Bessette Consultant for: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Celgene, Lilly, Novartis, Speakers bureau: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Lilly, Novartis, A. Chow Consultant for: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Speakers bureau: AbbVie, BMS, Janssen, Pfizer, Takeda, B. Haraoui Grant/research support from: AbbVie, Amgen, BMS, Janssen, Pfizer, Roche, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Janssen, Merck, Pfizer, Roche, and UCB, Speakers bureau: Amgen, BMS, Janssen, Pfizer, and UCB, V. Pavlova Consultant for: Amgen, Abbvie, BMS, Janssen, Lilly, Merk, Novartis, Roche, UCB, Pfizer, Speakers bureau: Amgen, Abbvie, BMS, Janssen, Lilly, Merk, Novartis, Roche, UCB, Pfizer, J. Stewart Consultant for: Pfizer, Abbvie, Amgen, Celgene, Roche, Novartis, V. Remple Shareholder of: AbbVie, Employee of: AbbVie

Background The Biologic Trial Registry Across Canada (BioTRAC) was a multi-centre, prospective, longitudinal, observational program that gathered and analysed data on inflammatory arthritis patients treated with infliximab (IFX), golimumab and ustekinumab. Patients specifically treated with IFX were recruited from July 2002 to June 2015 and followed up to June 2017. Objectives The objective of this abstract is to document the final consolidated safety data from the BioTRAC IFX cohort. Methods Treatment was prescribed by the physician per actual clinical practice or standard of care for rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA); there was no randomised assignments to treatment. There were no restrictions on the use of concomitant medications. At enrolment (baseline) and approximately every 6 months thereafter, information was collected to assess safety, clinical outcomes, quality of life, comorbidities, pharmaco-economics and treatment regimens. Results A total of 1390 patients were enrolled and used for this analysis. The proportion of patients by indication was 59.2% for RA (n=890), 25.9% for AS (n=389) and 7.4% for PsA (n=111). The mean (SD) exposure was 3.10 (3.26) years for a sum of 4290.25 patient-years. Treatment with IFX was generally safe, with AEs and SAEs being reported for 64.3% and 19.5% of patients, respectively. The incidence rate of AEs and SAEs was 116.0 and 11.2 events per 100 pt-years, respectively. More specifically, 338 SAEs were reported by 189 (21.2%) RA patients [SAEs/100 pt-yrs: 11.7], 130 SAEs were reported by 60 (15.4%) AS patients [SAEs/100 pt-yrs: 10.5] and 28 SAEs were reported by 22 (19.8%) PsA patients [SAEs/100 pt-yrs: 8.82]. The most commonly reported AE identified was arthralgia, viral upper respiratory tract infection, upper respiratory tract infection and nausea. For SAEs, the most commonly reported SOC (≥3% of patients) was “Infections and infestations” [5.3% (n=73); 2.16 SAEs/100 pt-yrs] and “Neoplasms benign, malignant and unspecified” [3.5% (n=49); 1.24 SAEs/100 pt-yrs] which occurred at similar rates to the general RA patient population1 and included two lymphomas [0.1%; 0.05/100 pt-yrs]. Across 3 closely monitored categories of AEs, a total of 302 closely monitored AEs were reported by 293 (21.1%) patients, including cancer (3.7%), lack of efficacy (17.1%) and tuberculosis (0.2%). A total of 21 deaths were reported during the study in 18 RA, 1 AS and 2 PsA patients. Cause of death included MACE (x5), lung cancer (x2), pulmonary fibrosis (x2), pneumonia (x2), respiratory failure, bronchitis, intestinal cancer, throat cancer, intestinal gangrene, disseminated TB, septic shock, procedural complication and drowning. The cause of death was not known for one patient. Conclusions The results of this longitudinal observational study showed that treatment with IFX was well tolerated in people living with AS, PsA and RA over a 15 year period in a real-world setting. Reference [1] Askling, et al. Arthritis & Rheum2009;60:3180–9. Disclosure of Interest D. Choquette Grant/research support from: Janssen Inc., P. Rahman Grant/research support from: Janssen Inc., Consultant for: Janssen Inc., Speakers bureau: Janssen Inc., A. Chow: None declared, R. Faraawi Consultant for: Janssen Inc., Speakers bureau: Janssen Inc., W. Olszynski Consultant for: Janssen Inc., E. Rampakakis: None declared, O. Asin-Milan Employee of: Janssen Inc., B. Osborne Employee of: Janssen Inc., A. Lehman Employee of: Janssen Inc., F. Nantel Shareholder of: Johnson and Johnson, Employee of: Janssen Inc.

Background COMPLETE-AS is an ongoing Canadian observational study of anti-TNFα naive adults with active AS per the judgment of the treating physician, who require change in current AS treatment to either 1 a subsequent NSAID or non-biologic disease modifying antirheumatic drug (nbDMARD group), or 2 to adalimumab (ADA group). Objectives The aim of this analysis was to describe and compare the baseline demographic and disease parameters of patients in the nbDMARD and ADA groups and to compare the 12 month effectiveness of the two treatment methods. Methods In the current analysis patients enrolled between July/2011 – Jun/2016 were included. Outcome measures analysed were extra articular manifestations (EAM 1: IBD, psoriasis, uveitis, enthesitis; EAM 2: IBD, uveitis, enthesitis), disease activity (BASDAI), functional status (BASFI), and quality of life (QoL; SF-12). Between-group differences in baseline parameters were assessed with the Chi-square test for categorical variables and the independent samples t-test for continuous variables. Baseline-adjusted changes in BASDAI and BASFI over time were compared between the two groups using linear mixed models. Results A total of 609 patients (nbDMARD n=177, ADA n=432) were included in the current analysis. No significant differences in baseline demographics were observed between the two groups. However, at baseline, patients initiating ADA were more likely to be unemployed (38% ADA vs. 27.1% nbDMARD, p = 0.009), had higher mean BASDAI (6.4 vs. 5.0; p After 12 months of treatment the prevalence of EAMs decreased significantly in the ADA group (EAM 1: p=0.004; EAM 2: p=0.033) but not in the nbDMARD group. After adjusting for baseline values, patients treated with ADA had numerically lower BASDAI score (least square means – LSM: 3.7 vs. 4.3, p=0.171) significantly lower BASFI score (2.9 vs. 3.6, p=0.031) scores, and comparable SF12-PCS (24.9 vs. 24.7, p=0.210) and SF12-MCS (19.1 vs. 18.9, p=0.532) scores at 12 months. During follow-up, 7.4% of ADA patients initiated another biologic and 23.7% of patients in the nbDMARD group initiated biologic treatment (p Conclusions AS patients initiating ADA in Canadian routine clinical care have significantly greater disease severity and impaired quality of life at baseline compared with those initiating non-biologic treatment. Treatment with ADA for 12 months resulted in greater reduction in the prevalence of EAMs and a greater reduction in disease severity scores compared to treatment with non-biologic agents. Acknowledgements JSS Medical Research, Montreal, Canada Disclosure of Interest L. Bessette Consultant for: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Celgene, Lilly, Novartis, Speakers bureau: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Lilly, Novartis, M. Khraishi Consultant for: AbbVie, Speakers bureau: AbbVie, A. Chow Consultant for: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Speakers bureau: AbbVie, BMS, Janssen, Pfizer, Takeda, V. Pavlova Grant/research support from: UCB, Consultant for: Amgen, Abbvie, BMS, Janssen, Lilly, Merk, Novartis, Roche, UCB, Pfizer, Speakers bureau: Amgen, Abbvie, BMS, Janssen, Lilly, Merk, Novartis, Roche, UCB, Pfizer, S. Silverberg Consultant for: AbbVie, Janssen, J. Stewart Consultant for: Pfizer, Abbvie, Amgen, Celgene, Roche, Novartis, V. Remple Shareholder of: AbbVie, Employee of: AbbVie

Objective: To compare anti-TNF dose escalation, DMARD and/or glucocorticoid intensification, switches to another biologic, and drug and drug-related costs over 12 and 18 months for rheumatoid arthritis (RA) patients initiating etanercept (ETN), adalimumab (ADA), or infliximab (IFX) in routine clinical practice across Canada. Methods: A retrospective chart review of biologic-naïve adult RA patients newly initiating ADA, ETN, or IFX between January 01, 2006 and December 31, 2012 from 11 practices across Canada. Results: There were 314 patients in the 12-month analysis and 217 in the 18-month analysis. No dose escalation occurred with ETN over 12 and 18 months versus 38% and 32% for IFX (p Patients initiating ETN had lower total (drug and drug-related) costs over 12 and 18 months compared to IFX, and no difference compared to ADA when adjusted for potential confounders. Patients with dose escalation had higher costs compared to those with no dose escalation. Conclusion: Physicians were more likely to escalate the dose of IFX, but optimize co-therapy with ADA and ETN. ETN patients had no dose escalation and were less likely to have DMARD and/or glucocorticoid intensification than ADA patients. ETN-treated patients had lower costs compared to IFX patients.

A critical benchmark in the development of antibody-based therapeutics is demonstration of efficacy in preclinical mouse models of human disease, many of which rely on immunodeficient mice. However, relatively little is known about how the biology of various immunodeficient strains impacts the in vivo fate of these drugs. Here we used immunoPET radiotracers prepared from humanized, chimeric, and murine mAbs against four therapeutic oncologic targets to interrogate their biodistribution in four different strains of immunodeficient mice bearing lung, prostate, and ovarian cancer xenografts. The immunodeficiency status of the mouse host as well as both the biological origin and glycosylation of the antibody contributed significantly to the anomalous biodistribution of therapeutic monoclonal antibodies in an Fc receptor-dependent manner. These findings may have important implications for the preclinical evaluation of Fc-containing therapeutics and highlight a clear need for biodistribution studies in the early stages of antibody drug development. Significance: Fc/FcγR-mediated immunobiology of the experimental host is a key determinant to preclinical in vivo tumor targeting and efficacy of therapeutic antibodies. Cancer Res; 78(7); 1820–32. ©2018 AACR.

The RACAT (Rheumatoid Arthritis Comparison of Active Therapies) trial found triple therapy to be noninferior to etanercept-methotrexate in patients with active rheumatoid arthritis (RA).To determine the cost-effectiveness of etanercept-methotrexate versus triple therapy as a first-line strategy.A within-trial analysis based on the 353 participants in the RACAT trial and a lifetime analysis that extrapolated costs and outcomes by using a decision analytic cohort model.The RACAT trial and sources from the literature.Patients with active RA despite at least 12 weeks of methotrexate therapy.24 weeks and lifetime.Societal and Medicare.Etanercept-methotrexate first versus triple therapy first.Incremental costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).The within-trial analysis found that etanercept-methotrexate as first-line therapy provided marginally more QALYs but accumulated substantially higher drug costs. Differences in other costs between strategies were negligible. The ICERs for first-line etanercept-methotrexate and triple therapy were $2.7 million per QALY and $0.98 million per QALY over 24 and 48 weeks, respectively. The lifetime analysis suggested that first-line etanercept-methotrexate would result in 0.15 additional lifetime QALY, but this gain would cost an incremental $77 290, leading to an ICER of $521 520 per QALY per patient.Considering a long-term perspective, an initial strategy of etanercept-methotrexate and biologics with similar cost and efficacy is unlikely to be cost-effective compared with using triple therapy first, even under optimistic assumptions.Data on the long-term benefit of triple therapy are uncertain.Initiating biologic therapy without trying triple therapy first increases costs while providing minimal incremental benefit.The Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, Canadian Institutes for Health Research, and an interagency agreement with the National Institutes of Health-American Recovery and Reinvestment Act.

Objective To describe the profile of rheumatoid arthritis (RA) patients treated with infliximab in Canadian routine care and to assess the real-world effectiveness and safety of infliximab. Methods Biologics-naive RA patients from the Biologic Treatment Registry Across Canada were stratified based on their enrollment year. Effectiveness was assessed with the changes in clinical/laboratory parameters and patient-reported outcomes and the achievement of minimal disease activity and remission. Safety was assessed with the incidence of treatment-emergent adverse events (AEs). Results Among 628 patients, 45.9%, 34.6%, and 19.6% were enrolled between 2002–2005, 2005–2008, and 2008–2011, respectively. Patients recruited in more recent years had significantly lower Disease Activity Score with a 28-joint count using the C-reactive protein level (DAS28-CRP), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), swollen joint count in 28 joints, tender joint count in 28 joints, physician's global assessment of disease activity, patient's global assessment of disease activity, Health Assessment Questionnaire disability index, pain, erythrocyte sedimentation rate, and CRP level (P < 0.01 for all). Patient management also changed with a trend to initiate infliximab after failure of fewer disease-modifying antirheumatic drugs (DMARDs). Six-month treatment with infliximab resulted in statistically significant and clinically important improvements in all disease parameters examined, which were sustained over 36 months. The cumulative probability of achieving remission by 36 months, as defined by the DAS28, SDAI, and CDAI, was 56.2 (95% confidence interval [95% CI] 47.8–64.8), 31.0 (95% CI 23.8–39.8), and 36.2 (95% CI 28.5–45.3), respectively, which was significantly greater in patients with lower baseline disease activity. The profile and incidence of AEs were comparable to data previously reported for tumor necrosis factor α inhibitors. Conclusion RA patient characteristics at infliximab initiation changed over time toward lower disease activity. Furthermore, a trend to treat patients with fewer DMARDs before initiation of infliximab was observed. However, treatment with infliximab was effective in significantly reducing disease activity independent of the treatment initiation year.

9006 Background: MET exon 14 alterations comprise a novel class of lung cancer drivers. MET tyrosine kinase inhibitors (TKIs) are active in patients with these cancers, but objective response rates (ORRs) are modest (~30%-40%). A subset of these cancers may harbor intrinsic resistance. Moreover, patients with initial benefit invariably develop acquired resistance. We set out to identify potential resistance mechanisms. Methods: We studied patients with stage IV MET exon 14-altered lung cancers who received a MET TKI. When feasible, tumor and/or plasma samples were collected, prioritizing paired pre- and post-TKI collection. Tumor samples underwent targeted mass spectrometry analysis (Nantomics) and DNA- (including MSK-IMPACT)/RNA-based (MSK-Fusion) next-generation sequencing (NGS). Plasma cfDNA underwent targeted NGS. ORR and progression-free survival (PFS) were assessed (RECIST v1.1). Results: 74 patients received a MET TKI (1 TKI n = 55; ≥2 TKIs n = 19). 91% received crizotinib as their 1st TKI. Pre-TKI MET levels in tumor tissue (range 0-2120 amol/µg) were associated with outcomes: ORR 63% (n = 7/11) and median PFS 6.9 mos with detectable MET vs ORR 0% (n = 0/5) and median PFS 4.6 mos with undetectable MET (HR for PFS 0.3). Pre-TKI RAS pathway activation was associated with response: ORR 0% (n = 0/6) with KRAS/NF1/RASA1 mutation vs ORR 29% (n = 25/87) in others. Similar outcomes were observed with pre-TKI KRAS expression (n = 16, all with detectable KRAS levels): ORR 0% (n = 0/2) in KRAS ≥700 amol/µg vs ORR 50% (n = 7/14) < 700 amol/µg. Acquired resistance (Jackman criteria) was seen in 29 patients, 9 with paired pre-/post-treatment samples. On-target acquired resistance was found in 2/9 patients (22%): MET D1228N (n = 1), HGF amplification (n = 1). Potential off-target acquired resistance mechanisms were found in 5/9 pts (44%): KRAS G13V (n = 1), RASA1 S742* (n = 1), MDM2 amplification (n = 2), EGFR amplification (n = 1). Conclusions: Lack of MET expression or RAS pathway activation is associated with poor MET TKI outcomes in MET exon14-altered lung cancers. On-target acquired resistance is found in < 25% of patients; HGF amplification is a novel mechanism. Off-target intrinsic/acquired resistance may be mediated by RAS/MDM2/EGFR pathway activation.

A role for macrophages in erythropoiesis was suggested several decades ago when erythroblastic islands in the bone marrow, composed of a central macrophage surrounded by developing erythroblasts, were described. However, the in vivo role of macrophages in erythropoiesis under homeostatic conditions or in disease remains unclear. We found that specific depletion of CD169(+) macrophages markedly reduced the number of erythroblasts in the bone marrow but did not result in overt anemia under homeostatic conditions, probably because of concomitant alterations in red blood cell clearance. However, CD169(+) macrophage depletion significantly impaired erythropoietic recovery from hemolytic anemia, acute blood loss and myeloablation. Furthermore, macrophage depletion normalized the erythroid compartment in a JAK2(V617F)-driven mouse model of polycythemia vera, suggesting that erythropoiesis in polycythemia vera remains under the control of macrophages in the bone marrow and splenic microenvironments. These results indicate that CD169(+) macrophages promote late erythroid maturation and that modulation of the macrophage compartment may be a new strategy to treat erythropoietic disorders.

Purpose: To quantitatively characterize the longitudinal dose exposure–response [urinary N-telopeptide normalized to urinary creatinine (uNTx/Cr) suppression] relationship for denosumab in patients with bone metastases from solid tumors. Experimental Design: Data from 373 patients who received denosumab as single or multiple subcutaneous doses ranging from 30 to 180 mg (or 0.01 to 3 mg/kg) administered every 4 or 12 weeks for up to 3 years were used in this analysis. An inhibitory sigmoid IMax model was used to characterize the time course of uNTx/Cr as a function of serum denosumab concentrations and the M3 method was used to analyze the 52% of uNTx/Cr values below the limit of quantification in the context of a mixed-effects model. Age, weight, sex, race, and cancer type were evaluated as potential covariates for model parameters. Model-based simulations were undertaken to explore and predict the role of denosumab dose and dosing intervals on uNTx/Cr suppression. Results: The typical value (between-subject variability; %) for uNTx/Cr at baseline was 49.2 nmol/L/mmol/L (76.8%), denosumab maximal uNTx/Cr suppression (efficacy) was 93.7% (127%), and the denosumab concentration providing half-maximal uNTx/Cr suppression (potency) was 31.8 ng/mL (287%). No effect of covariates on denosumab efficacy and potency was identified. Simulations indicated that a s.c. denosumab dose of 120 mg administered every 4 weeks provides more than 90% suppression of uNTx/Cr in the maximum proportion of patients relative to other every 4- and 12-week doses evaluated. Conclusions: Over the wide range of dosing regimens examined, a s.c. denosumab dose of 120 mg administered every 4 weeks is the optimal dosing regimen to suppress uNTx/Cr in patients with bone metastases from solid tumors. Clin Cancer Res; 18(9); 2648–57. ©2012 AACR.

What is already known about this subject • Several clinical studies have shown that the toxicity of tipifarnib in cancer patients is acceptable. • However, previous exposure vs. toxicity analyses have been only performed for a limited range of toxic effects and were based on a single study involving a limited number of patients. What this study adds • This study represents the first comprehensive and large-scale exposure vs. response analysis based on five clinical studies, involving more than 600 patients and evaluating more than 10 different toxicities. • The results have defined the relationship between haematological toxicities and tipifarnib exposure in patients with solid tumours. The occurrence of exposure-related nonhaematological toxicities was low regardless of tumour type. Aims To explore the potential relationship between systemic exposure to tipifarnib and the incidence of toxicity in cancer patients. Methods Data from 673 subjects (540 receiving tipifarnib and 133 receiving placebo) were included in the analysis. Tipifarnib was administered in doses ranging from 100 mg to 850 mg twice daily under fed conditions for 21 days in a 28 day cycle. Univariate and multivariate logistic regression models were used to evaluate the relationships between tipifarnib exposure and haematological (neutropenia and thrombocytopenia) and nonhaematological toxicities. Tipifarnib exposure was quantified as the area under the curve during the first cycle of chemotherapy (AUC), the maximum plasma concentration (Cmax), the time above plasma tipifarnib concentrations of 400 (T400) and 600 ng ml−1 (T600), the cumulative area under the curve (AUCT), and the area under the curve density (AUCD), defined as the ratio AUCT to the duration of treatment. The nonhaematological toxicities measured were elevation of AST, ALT, bilirubin and serum creatinine, the occurrence of a skin rash, CNS or peripheral neuropathy, nausea and vomiting, diarrhoea and inflammation of the gastrointestinal tract. Odds ratios (OR) associated with drug exposure were used to measure the effect of the drug. Results Tipifarnib AUC exhibited a positive and significant association with neutropenia grade ≥3 (OR 1.69, 95% CI 1.47, 1.95) and thrombocytopenia grade ≥3 (OR 1.41, 95% CI 1.21, 1.63) in patients with solid tumours, but not in refractory or relapsed AML patients. The incidence of exposure-related nonhaematological toxicity is small regardless of tumour type. No association was found between tipifarnib AUC and the elevation of AST, ALT and total bilirubin, and nausea and vomiting. There was a weak relationship between tipifarnib AUC and serum creatinine elevation (OR 1.18, 95% CI 1.11, 1.26), CNS (OR 1.05, 95% CI 1.01, 1.10) and peripheral neurotoxicity (OR 1.10, 95% CI 1.03, 1.18), diarrhoea (OR 1.14, 95% CI 1.08, 1.21), gastrointestinal tract inflammation (OR 1.13, 95% CI 1.07, 1.19), and skin rash (OR 1.10, 95% CI 1.04, 1.17). Conclusions In those patients who develop severe toxicity, dose reduction may improve the tolerability of tipifarnib. However, an exposure-guided approach to dosage adjustment to limit haematological and nonhaematological toxicity is not warranted.

Purpose: To compare the rejection rates, graft failure rates, mean visual, keratometric and refractive outcomes of combined penetrating keratoplasty and cataract extraction with penetrating keratoplasty alone. Methods: A retrospective study of all patients who had combined keratoplasty and cataract extraction/intraocular lens insertion (49 eyes; mean age 65.3 years; mean follow up 17 months) compared with all patients who had keratoplasty only (58 eyes; mean age 64.0 years; mean follow up 14 months). Results: One hundred and seven eyes in 99 patients had keratoplasty in the period and were included in the study. The most common indication for keratoplasty in patients who had triple procedures was Fuchs' endothelial dystrophy (24.5%). During the study seven (6.5%) grafts failed and four (3.7%) had allogenic rejection without failure during this period. There was no statistical difference between the graft survival rates of the two study groups. The mean postoperative logMAR visual acuity (VA) was 0.42 and postoperative VA of 6/12 or better was seen in 71% of patients. Mean postoperative corneal curvature was 44.6 dioptres (D), mean corneal astigmatism was −4.0 D and was ≥5 D in 38%. Mean double-angle Cartesian coordinates for corneal astigmatism were x−0.87 D and y−0.29 D. Mean best sphere of postoperative refractions was −0.61 D and mean absolute refractive error was 2.2 D. There was no statistically significant difference in VA, keratometric or refractive outcome measures between the two study groups. Conclusion: Over a short follow up, keratoplasty combined with cataract extraction/intraocular lens insertion showed a similar risk of graft failure or allogenic graft rejection when compared with keratoplasty alone and we recommend the triple procedure for quicker visual recovery and less operative procedures.

Objective.Infliximab (IFX) is a therapeutic monoclonal antibody targeting tumor necrosis factor-α indicated in the treatment of chronic inflammatory diseases. IFX is administered by intravenous infusion and may be associated with different types of infusion reactions.Methods.RemiTRAC Infusion (NCT00723905) is a Canadian observational registry in which patients receiving IFX are followed prospectively to document premedication use, adverse events, infusion reactions, and the management of infusion reactions. The primary endpoint was to assess factors associated with infusion reactions.Results.There were 1632 patients enrolled and 24,852 infusions recorded. Most patients (63.1%) were treated for rheumatologic conditions such as rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis. Of the 1632 patients, 201 (12.3%) reported at least 1 infusion reaction. Three hundred twenty-two infusions were associated with an infusion reaction (1.3%), and most were mild to moderate in severity (95%). The most common infusion reactions were pruritus (19.9%), flushing (9.9%), or dyspnea (6.2%). Multivariate analysis showed that antihistamines premedication, number of previous infusion reactions, and female sex were significantly associated with an increased incidence of infusion reactions (p < 0.0011). The use of any concomitant immunosuppressant or corticosteroids did not influence the incidence of infusion reactions. Antihistamine premedication was associated with an increased incidence of infusion reactions (OR 1.58, p = 0.0007).Conclusion.This registry shows that in community-based infusion clinics, infusion reactions to IFX are uncommon and mild to moderate in nature. Antihistamines, intravenous steroids, and acetaminophen are widely used as preventative premedication, although this study showed an absence of benefit with their use.

ObjectiveTo describe the minimal disease activity (MDA) rate over time in patients with psoriatic arthritis (PsA) receiving antitumour necrosis factor agents, evaluate prognostic factors of MDA achievement and identify the most common unmet criteria among MDA achievers.DesignBiologic Treatment Registry Across Canada (BioTRAC): ongoing, prospective registry of patients initiating treatment for rheumatoid arthritis, ankylosing spondylitis or PsA with infliximab (IFX), golimumab (GLM) or ustekinumab.Setting46 primary-care Canadian rheumatology practices.Participants223 patients with PsA receiving IFX (enrolled since 2005) and GLM (enrolled since 2010) with available MDA information at baseline, 6 months and/or 12 months.Primary and secondary outcome measuresMDA was defined as ≥5 of the following criteria: 28-item tender joint count (TJC28) ≤1, 28-item swollen joint count (SJC28) ≤1, Psoriasis Area and Severity Index (PASI) ≤1 or body surface area≤3, Pain Visual Analogue Scale (VAS) ≤15 mm, patient’s global assessment (PtGA) (VAS) ≤20 mm, Health Assessment Questionnaire (HAQ) ≤0.5, tender entheseal points ≤1. Independent prognostic factors of MDA achievement were assessed with multivariate logistic regression.ResultsMDA was achieved by 11.7% of patients at baseline, 43.5% at 6 months, 44.8% at 12 months and 48.8% at either 6 or 12 months. Among MDA achievers at 6 months, 75.7% had sustained MDA at 12 months. Lower baseline HAQ (OR=0.210; 95% CI: 0.099 to 0.447) and lower TJC28 (OR=0.880; 95% CI: 0.804 to 0.964), were significant prognostic factors of MDA achievement over 12 months of treatment. The most commonly unmet MDA criteria among MDA achievers was patient reported pain (25%), PtGA (15%) and PASI (12%).ConclusionsAlmost 50% of patients treated with IFX or GLM in routine clinical care achieved MDA within the first year of treatment. Lower baseline HAQ and lower TJC28, were identified as significant prognostic factors of MDA achievement. The most commonly unmet criteria in patients who achieved MDA were pain, PtGA and PASI.Trial registration numberBioTRAC (NCT00741793).

Summary To guide the design of immunotherapy strategies for patients with early stage lung tumors, we developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single-cell analysis of the tumor, non-involved lung, and blood cells, we provide a detailed immune cell atlas of early lung tumors. We show that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments. Moreover, we identified changes in tumor-infiltrating myeloid cell (TIM) subsets that likely compromise anti-tumor T cell immunity. Paired single-cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies. Video Abstract

Objectives To describe the profile of patients with ankylosing spondylitis (AS) treated with infliximab in Canadian routine care and to assess the effectiveness and safety of infliximab in real world. Setting 46 primary care rheumatology practices across Canada. Participants 303 biological-naïve patients with AS or patients previously treated with a biological for

Diagnosing and treating depression in a primary care practice is an important, yet difficult task, especially for safety-net practices serving the uninsured. In the United States healthcare system, there is a mismatch between the need for mental health care and access to services. This disparity is most striking among the uninsured. Mental health disorders are more prevalent among the uninsured, and even when diagnosed with mental illness, they are less likely to obtain necessary treatment than insured patients. Given the increasing burden of depression on society, growing numbers of uninsured and negative repercussions of untreated mental illness, improvements in screening and management protocols are becoming more important in primary care practices serving this population. The quality of depression treatment at commercial and public insurance plans in New York City (NYC) and New York State (NYS) were compared to that of the East Harlem Health Outreach Partnership (EHHOP), the student-run clinic of the Mount Sinai School of Medicine. Based on the comparison, the study made recommendations for an integrated, on-site mental health service program at the community health clinic. A cohort of 49 depressed patients were evaluated and treated at the EHHOP clinic. The quality of the mental health care was evaluated according to variables from the Healthcare Effectiveness Data and Information Set (HEDIS). Indicators of quality included demographics, method of diagnosis, type of pharmacological treatment, referral to specialty care, patient adherence to follow-up care and adherence to pharmacologic treatment. When compared to insured patients in NYS, more EHHOP patients had the appropriate number of physician contacts after being diagnosed with depression than patients with commercial health plans (P = 0.008) and Medicaid (P = 0.09). Similarly, a greater number of EHHOP patients had better acute phase (P = 0.001; P = 0.096) and continuous phase (P = 0.049; P = 0.88) pharmacologic treatment than patients with commercial health plans and Medicaid, respectively. EHHOP meets and, in some areas, exceeds the quality of depression treatment when compared to insured populations. Even though EHHOP already surpasses these indicators, the clinic can improve its diagnostic capabilities, prescription medication adherence, and referral care follow-through by creating an on-site mental health clinic.

Host macrophages protect against graft-versus-host disease in part by engulfing donor T cells and inhibiting their proliferation., Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.

Graft-versus-host disease (GVHD) is a serious complication of allogeneic bone marrow transplantation, and donor T cells are indispensable for GVHD. Current therapies have limited efficacy, selectivity, and high toxicities. We used a novel flow cytometry technique for the analysis of intracellular phosphorylation events in single cells in murine BMT models to identify and validate novel GVHD drug targets.1-7 This method circumvents the requirement for large numbers of purified cells, unlike western blots. We defined a signaling profile for alloactivated T cells in vivo and identified the phosphorylation of ERK1/2 and STAT-3 as important events during T-cell (allo)activation in GVHD. We establish that interference with STAT-3 phosphorylation can inhibit T-cell activation and proliferation in vitro and GVHD in vivo. This suggests that phospho-specific flow cytometry is useful for the identification of promising drug targets, and ERK1/2 and STAT-3 phosphorylation in alloactivated T cells may be important for GVHD.

To determine the mechanisms of graft-versus-tumor (GVT) activity in the absence of graft-versus-host disease (GVHD) against a solid tumor, we established two allogeneic bone marrow transplantation models with a murine renal cell carcinoma (RENCA). The addition of 0.3 × 106 donor CD8+ T cells to the allograft increased the survival of tumor-bearing mice without causing GVHD. The analysis of CD8+ T cells deficient in cytotoxic molecules demonstrated that anti-RENCA activity is dependent on IFN-γ and Fas ligand (FasL), but does not require soluble or membrane-bound TNF-α, perforin, or TRAIL. Recipients of IFN-γ−/− CD8+ T cells are unable to reject RENCA compared with recipients of wild-type CD8+ T cells and, importantly, neither group develops severe GVHD. IFN-γ−/− CD8+ T cells derived from transplanted mice are less able to kill RENCA cells in vitro, while pretreatment of RENCA cells with IFN-γ enhances class I and FasL expression and rescues the lytic capacity of IFN-γ−/− CD8+ T cells. These results demonstrate that the addition of low numbers of selected donor CD8+ T cells to the allograft can mediate GVT activity without lethal GVHD against murine renal cell carcinoma, and this GVT activity is dependent on IFN-γ and FasL.

Tumor necrosis factor (TNF) plays an important role in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) activity after allogeneic bone marrow transplantation (allo-BMT). TNF can be expressed in a membrane-bound form (memTNF) and as a soluble (solTNF) molecule after being cleaved by the TNF-α converting enzyme (TACE). To study the contribution of donor T-cell–derived memTNF versus solTNF in GVHD and GVT, we used mice containing a noncleavable allele in place of endogenous TNF (memTNFΔ/Δ) as donors in murine BMT models. Recipients of memTNF T cells developed significantly less GVHD than recipients of wild-type (wt) T cells. In contrast, GVT activity mediated by memTNF T cells remained intact, and alloreactive memTNF T cells showed no defects in proliferation, activation, and cytotoxicity. These data suggest that suppressing the secretion of solTNF by donor T cells significantly decreases GVHD without impairing GVT activity.

Background Despite the importance of the Health Assessment Questionnaire (HAQ) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in assessing patient-reported functional status and disease activity, they have been critiqued for being time-consuming, not convenient on a daily-basis and thus not contributing to decisions in routine care. Objectives The aim of this analysis was to describe the correlation of individual HAQ and BASDAI questions with patient and physician reported measures used in AS and to examine whether the instruments could be reduced to better reflect routine clinical practice. Methods BioTRAC is an ongoing prospective registry of patients initiating infliximab or golimumab. Data from AS patients treated in 2005-2014 were used. The correlation of individual HAQ and BASDAI questions with patient (pain, BASDAI, HAQ and BASFI) and physician (MDGA) reported measures was described with the Pearson9s correlation coefficient. The impact of each question on the need for help in each HAQ domain was assessed with logistic regression. Factor analysis was used to assess the variability due to each individual question in HAQ and BASDAI. Results A total of 413 AS patients with 1660 BASDAI and 1654 HAQ assessments were included. HAQ and BASDAI questions correlated at different extents with each AS measure. Questions related to “eating” and “gripping” showed the lowest correlation with patient and physician reported measures. All HAQ questions had higher correlations with patient reported measures than with MDGA. The BASDAI question on “fatigue and tiredness” showed the highest correlation with BASFI, while the question on “other joints pain/swelling” showed the lowest correlation with MDGA. None of the HAQ and BASDAI questions were associated with needing help for eating. All other HAQ individual questions were significantly associated with the need for help within their corresponding category, with the exception of Q5C and Q7A. BASDAI question on level of discomfort was significantly associated with the need for help in all HAQ categories, with the exception of “eating” and “walking”. Q2A and Q7C accounted for 59.6% of the HAQ variance. The level of morning stiffness accounted for 73.8% of the BASDAI variance. When combining the HAQ and BASDAI, Q2A and Q3A from HAQ and Q1 from BASDAI accounted for 63.5% of the variance. Conclusions Variability exists in the correlation of HAQ and BASDAI questions with patient and physician reported AS measures. The results suggest that “standing up straight from an armless chair” and “turning faucets on/off” are the main drivers of HAQ, while the level of morning stiffness drives the BASDAI. Three questions were found to drive the combined HAQ and BASDAI which may have implications in the design of self-report instruments. Disclosure of Interest P. Rahman Consultant for: Abbott, AbbVie, Amgen, BMS, Celgene, Janssen, Novartis, Pfizer, Roche, M. Zummer: None declared, W. Olszynski: None declared, M. Khraishi: None declared, D. Sholter: None declared, R. Faraawi Consultant for: Janssen, W. Bensen Consultant for: Janssen, M. Baker: None declared, A. Chow: None declared, J. Vaillancourt Employee of: JSS Medical Research, J. Sampalis Shareholder of: JSS Medical Research, F. Nantel Employee of: Janssen, S. Otawa Employee of: Janssen, A. Lehman Employee of: Janssen, C. Tkaczyk Employee of: Janssen, M. Shawi Employee of: Janssen

Background People with rheumatoid arthritis (RA) and other chronic diseases adjust their lifestyle to accommodate symptoms and limitations. Objectives The aim of the current analysis was to assess the utilization of aids/devices or help over time and to determine whether development of self-management behavior is responsible for HAQ improvement in RA patients on anti-TNF treatment in a real-world clinical practice setting. Methods BioTRAC is an ongoing, prospective registry of patients initiating treatment for RA, AS, or PsA with IFX or GLM. Data were used from RA patients treated with infliximab (IFX) between 2002-2014 or with golimumab (GLM) between 2010-2014. The correlation between the standard HAQ disability index (HAQ-DI) and the alternative disability index (HAQ-ADI), incorporating or not the use of aids/devices/help, respectively, was assessed with the Pearson9s correlation coefficient. Changes in HAQ-DI, HAQ-ADI, the individual HAQ domain scores, or the difference between HAQ-DI and HAQ-ADI over time, were assessed with general linear models. The slope of HAQ-DI and HAQ-ADI improvement in each patient was assessed with the paired-samples t-test. Results 1030 RA patients were included with a mean (SD) age of 56.1 (13.5) years and time since diagnosis of 8.5 (9.1) years. Mean (SD) DAS28, CDAI, HAQ-DI and HAQ-ADI scores at baseline were 5.6 (1.5), 34.3 (16.6), 1.59 (0.71), 1.47 (0.73), respectively. At baseline, highest HAQ domain scores included “Activities”, “Reach”, “Hygiene”, and “Grip”. The use of aids/devices/help was highest for these activities (49.2%, 47.5%, 38.0%, 73.1% of patients, respectively), with females requesting significantly more aids/devices/help than males. Treatment for 60 months resulted in statistically significant and clinically meaningful improvements in HAQ-DI and HAQ-ADI, and in significantly lower utilization of aids/devices/help. A statistically significant difference (P=0.001) was observed in the slope of HAQ-DI (Δ=-0.034/month) and HAQ-ADI (Δ=-0.038/month) improvement over time which could be attributed to the differential rate of use of aids/devices/help over time resulting in the inflation of HAQ-DI. The duration of follow-up was significantly (P Conclusions Our results have shown that problems with “Activities”, “Reaching”, “Hygiene”, and “Gripping” represent primary challenges in RA. Anti-TNF treatment resulted in significant improvements in all HAQ domains. Significant differences were observed over time, however, between HAQ-DI and HAQ-ADI suggesting that RA patients may also adjust their lifestyle to accommodate their symptoms. These findings highlight the importance of educational programs focused on self-management behaviors in RA. Disclosure of Interest D. Sholter Consultant for: Janssen, W. Olszynski Consultant for: Janssen, P. Baer Consultant for: Janssen, M. Sheriff Consultant for: Janssen, S. Dixit Consultant for: Janssen, A. Chow: None declared, B. Haraoui Consultant for: Janssen, D. Choquette Consultant for: Janssen, J. Kelsall Consultant for: Janssen, J. Sampalis: None declared, E. Rampakakis: None declared, F. Nantel Employee of: Janssen, C. Tkaczyk Employee of: Janssen, A. Lehman Employee of: Janssen

Background The Health Assessment Questionnaire (HAQ) is commonly used for assessing patient-reported functional status and disease activity in psoriatic arthritis (PsA). However, it has been critiqued for being time-consuming, not easily scored and thus, not contributing to decisions in routine care (1) Objectives The aim of this analysis was to describe the correlation of individual HAQ questions with patient and physician reported measures used in PsA and to examine whether the instrument could be reduced to better reflect routine clinical practice. Methods BioTRAC is an ongoing, prospective registry of patients initiating treatment for RA, AS, or PsA with infliximab or golimumab. Data from PsA patients treated with infliximab or golimumab in 2006-2013 were used. The correlation of each HAQ question with patient and physician (pain, patient global assessment (PtGA), SJC28, TJC28 and physician global assessment (MDGA)) reported measures were described with the Pearson9s correlation coefficient. The impact of each HAQ question on the need for help in each HAQ domain was assessed with logistic regression. Factor analysis was used to assess the variability due to each question in HAQ. Results A total of 183 PsA patients with 596 HAQ assessments were included. Individual HAQ questions correlated at different extents with each PsA measures. All questions showed higher correlations with PtGA and pain compared to MDGA. Regarding patient reported outcomes, Question 5A (“Wash/dry your entire body”) showed the highest correlation, specifically with pain. The majority of HAQ questions were significantly associated with the need for help within their corresponding ability category, with the exception of questions Q3B, Q3C, Q4B, Q5C and Q8B. The results of factor analysis showed that 2 (Q1A and Q3B) out of the 20 HAQ questions accounted for 61.5% of its matrix variance, suggesting that the question on the ability to “dress, tie shoelaces and do buttons”, as well as the question on the ability to “lift a full cup or glass” may be the main drivers of HAQ in PsA. Conclusions Variability exists in the correlation of individual HAQ questions with patient and physician reported PsA measures. Pain and PtGA are significantly associated with the various domains of HAQ, while clinical outcomes (SJC28 and TJC28) and MDGA are less important. Among PsA patients, the HAQ is driven by components related to dressing and grooming and to eating abilities, suggesting that PsA patients may be facing different challenges than RA patients. This may have implications from an occupational health perspective and in the design of a shorter self-report instrument more suitable for PsA patients. References Khanna D, et al. Arthritis Care Res. 2011;63:S486-S490. Disclosure of Interest D. Choquette Consultant for: AbbVie, Amgen, Celgene, BMS Canada, Janssen, Pfizer, C. Thorne: None declared, M. Khraishi: None declared, I. Fortin: None declared, R. Arendse: None declared, A. Chow: None declared, J. Kelsall Consultant for: Janssen, M. Baker: None declared, J. Vaillancourt Employee of: JSS Medical Research, J. Sampalis Shareholder of: JSS Medical Research, F. Nantel Employee of: Janssen, S. Otawa Employee of: Janssen, A. Lehman Employee of: Janssen, C. Tkaczyk Employee of: Janssen, M. Shawi Employee of: Janssen

Background Spondyloarthritis, including psoriatic arthritis (PsA), is characterized by inflammatory arthritis affecting axial and peripheral joints. It is commonly associated with extra-articular and peri-articular manifestations (PAMs) including dactylitis and enthesitis. Objectives To evaluate the point prevalence of enthesitis and dactylitis at the time of anti-TNF initiation, their impact on disease severity, and their evolution over time in patients with active PsA treated in a routine clinical practice setting. Methods BioTRAC is an ongoing, prospective registry of patients initiating treatment for rheumatoid arthritis (RA), ankylosing spondylitis (AS), or PsA with infliximab or golimumab as first biologics or after having been treated with a biologic for

Objectives Patient (PtGA) and physician (MDGA) global assessment of disease activity measure the same construct from two different perspectives. The objective of this study was to assess the agreement between these two measures over time as ascertained in Canadian routine clinical practice in patients with RA treated with infliximab or golimumab. Methods BioTRAC is an ongoing, prospective registry of patients initiating treatment for rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA) with infliximab or golimumab as first biologics or after having been treated with a biologic for less than six months. In this analysis, people with RA treated with infliximab who were enrolled between 2002 and 2012 and had at least one follow-up assessment and up to 60 months of follow up were included. PtGA and MDGA were measured on a 10-point Numerical rating scale (NRS) and 10 cm visual analog scale (VAS), respectively. The association between treatment duration and difference between MDGA and PtGA was assessed with linear regression. Internal consistency was assessed with the intra-class correlation coefficient (ICC) and Cronbach9s alpha (CA). Results A total of 675 patients assessed over 4193 visits during a mean follow up time of 20 months were included in the analyses. The overall mean (SD) PtGA and MDGA was 3.73 (2.89) and 3.38 (2.67), respectively (P Conclusions The results of this Canadian longitudinal observational registry have shown that there is poor agreement between physician-based and patient-based assessments of disease activity. In addition, the rate of reduction in disease activity over time is considerably higher when rated by physicians when compared to patients. In this chronic condition, physicians should be aware of this increasing discordance between the patient and physician global when making treatment decisions and managing patient expectations over time. Acknowledgements We thank Dr. Mary Bell, Sunnybrook Health Sciences Centre, for her contribution to the development of this analysis. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3902

Background Assessment of functional (dis)ability in rheumatoid arthritis (RA) is subject to patient judgment when appraising their ability to do daily activities. Objectives The aim of this analysis was to describe the impact of specific joint involvement on patient reported outcomes (PROs) - functional activity, pain and patient global assessment of disease activity (PtGA) - and to identify joints most resistant to treatment over time. Methods Biologic Treatment Registry Across Canada (BioTRAC) is an ongoing, prospective, registry of patients initiating treatment for RA, AS, or PsA with infliximab or golimumab as first biologics or after having been treated with a biologic for less than six months. In this analysis, data were included from RA patients treated with infliximab between 2002 and 2012 or with golimumab between 2010 and 2012. Based on joint involvement seven groups were created: shoulder(s), elbow(s), metacarpophalangeal (MCP), wrist(s), proximal interphalangeal (PIP), knee(s), and thumb(s). The impact of specific joints on patient outcomes was assessed with the independent-samples t-test. Linear regression was used in order to produce adjusted estimates. Results A total of 935 RA patients with 4,854 assessments were included. Swelling, tenderness, and swelling and/or tenderness in all joint groups were associated with significantly (P Conclusions Significant variability in PROs exists based on the presence of swelling and/or tenderness in specific joint groups. Swelling/tenderness of shoulders, wrists, knees and elbows were the main drivers of HAQ-DI, PtGA and pain. The results have important implications for the achievement of disease remission and suggest that the joint type in addition to the number of affected joints has unique impact on PROs. Disclosure of Interest R. Arendse: None declared, W. Bensen: None declared, A. Chow: None declared, J. Rodrigues: None declared, S. Dixit: None declared, D. Sholter: None declared, P. Baer: None declared, M. Baker: None declared, D. Choquette: None declared, I. Fortin: None declared, A. Jovaisas: None declared, E. Rampakakis: None declared, J. Sampalis: None declared, F. Nantel Employee of: Janssen Inc Canada, S. Otawa Employee of: Janssen Inc Canada, M. Shawi Employee of: Janssen Inc Canada, A. Lehman Employee of: Janssen Inc Canada DOI 10.1136/annrheumdis-2014-eular.5185

Background The efficacy of anti-TNF in the management of psoriatic arthritis (PsA) and rheumatoid arthritis (RA) has been demonstrated in numerous controlled clinical trials. Objectives The objective of this analysis was to assess in Canadian routine clinical practice the durability of treatment with infliximab (IFX) in PsA and RA and the determinants associated with sustainability of IFX. Methods BioTRAC is an ongoing, prospective registry of patients initiating treatment for RA, AS, or PsA with infliximab or golimumab as first biologics or after having been treated with a biologic for less than six months. Patients with PsA or RA treated with IFX who were enrolled between 2002 (2005 for PsA patients) and 2012 were included in this analysis. Dose optimization was defined as an increase in the frequency and/or dosing of IFX. Kaplan Meier (KM) estimates and Cox proportional models were used in the analysis. Results A total of 92 PsA and 830 RA patients were included in the analysis. Mean (SD) age of the PsA and RA patient cohorts was 48.7 (9.9) and 55.8 (13.4) years, respectively, and mean (SD) duration since diagnosis was 6.8 (9.1) and 10.2 (10.1) years, respectively. Twenty seven (29.3%) PsA patients and 407 (49.0%) RA patients had discontinued treatment. Overall KM-based mean (SE) duration of treatment was 41.4 (3.6) months and 61.3 (2.2) months for PsA and RA patients, respectively. Longer treatment duration was associated with significantly greater improvements in pain (parameter estimate PsA: -0.21, P=0.020; RA: -0.27, P Conclusions The results of this observational study have shown a high durability of treatment with IFX for patients with PsA or RA in a real-world setting. Concomitant medication use significantly impacts treatment durability. Furthermore, longer disease duration, higher TJC, less severe skin disease at initiation and previous biologic use in PsA, and absence of IFX dose optimization in RA, may be associated with reduced treatment durability. Disclosure of Interest J. Kelsall: None declared, A. Jovaisas: None declared, P. Rahman: None declared, D. Sholter: None declared, M. Starr: None declared, W. Bensen: None declared, M. Sheriff: None declared, W. Olszynski: None declared, M. Zummer: None declared, R. Faraawi: None declared, A. Chow: None declared, S. Kapur: None declared, E. Rampakakis: None declared, J. Sampalis: None declared, F. Nantel Employee of: Janssen Inc Canada, S. Otawa Employee of: Janssen Inc Canada, M. Shawi Employee of: Janssen Inc Canada, A. Lehman Employee of: Janssen Inc Canada DOI 10.1136/annrheumdis-2014-eular.4013

Background Achievement of clinical remission in rheumatoid arthritis (RA) is a process that may take several months. Identification of clinical signs predicting future remission may assist physicians in clinical decision making. Objectives The aim of this analysis was to describe the association between DAS28-ESR scores at 6 months and remission at 12 months in RA patients treated with infliximab (IFX) in a real-world, clinical practice setting. Methods BioTRAC is an ongoing, prospective Canadian registry of patients initiating treatment for RA, ankylosing spondylitis (AS), or psoriatic arthritis (PsA) with IFX or golimumab as first biologics or after having been treated with a biologic for Results A total of 293 patients were included with a mean (SD) age of 56 (13.5) years and disease duration of 10.0 (9.7) years. Mean (SD) DAS28 was 3.8 (1.5) and 3.5 (1.5) at 6 and 12 months, respectively, and the percent with DAS28-ESR remission was 24.6% and 27.0%. Of the patients in remission at 6 months, 65.3% sustained the remission at 12 months, while of those not in remission at 6 months, 14.5% achieved remission at 12 months (P Conclusions The results of this analysis demonstrate that a DAS28-ESR target of ≤3.54 at 6 months maximizes the likelihood of remission at 12 months while a value of ≤2.13 should be targeted for optimal sustainment of remission. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4755