OP0179 USEFUL STUDY I: A MULTICENTRE LONGITUDINAL STUDY TO TEST WHETHER ULTRASOUND CAN IDENTIFY PATIENTS WITH MUSCULOSKELETAL SYMPTOMS OF LUPUS WITH BETTER RESPONSE TO THERAPY

Background:In SLE, musculoskeletal manifestations impact on quality of life and trial outcomes. We previously showed that assessments based on joint swelling lack sensitivity, specificity and responsiveness compared to ultrasound (US).Objectives:To determine clinical features predicting US synovitis and whether patients with US synovitis respond better to therapyMethods:SLE patients were recruited if the referring physician deemed they had inflammatory pain warranting treatment. Swollen joints were not required. At baseline, physicians recorded features of inflammation, concurrent fibromyalgia and osteoarthritis. Stable doses of prednisolone (≤5mg/day), antimalarials or immunosuppressants were allowed. Participants received depomedrone 120mg IM then were assessed at 0, 2 and 6 weeks for 66/68 swollen and tender joint counts, BILAG-2004, SLEDAI-2K, physician global and MSK-VAS, inflammatory markers, patient pain and disease activity-VAS, HAQ-DI, LupusQoL, US of hands and wrists (blinded to patient and clinical assessor). An internal pilot determined the primary endpoint:(Early Morning stiffness-VAS (EMS-VAS) at 2 weeks (adjusted for baseline) between patients with US-synovitis (GS≥2 or PD≥1 in ≥1 joint) vs. normal US at baseline. 20% difference was considered clinically meaningful. Sensitivity analyses adjusted for prednisolone and immunosuppressants.Results:122/133 patients completed all visits. There was significant disagreement between clinical examination and US. 78/133 had US synovitis; 68% of these had ≥1 swollen joint. Of 66/133 patients with ≥ 1 swollen joint, 20% had normal US. US-synovitis was more likely with joint swelling, a symmetrical small joint distribution and active serology. Physician-determined EMS, other lupus features or prior response to therapy were not associated. Fibromyalgia or osteoarthritis did not reduce the probability of US synovitis.In the full analysis set (n=133) there was no difference in EMS VAS at 2 weeks according to US synovial status at baseline (difference -8mm, 95% CI -19, 4mm, p=0.178). 32 patients had fibromyalgia. After excluding them, we found a statistically and clinically significantly better clinical response to depomedrone in patients with US-synovitis at baseline (baseline-adjusted EMS VAS at 2 weeks -12mm, 95% CI -24, 0mm, p=0.049). This difference was greater in the treatment-adjusted sensitivity analysis (-12.8 (95% CI -22, -3mm), p=0.007) and the per-protocol-adjusted sensitivity analysis (-14.8mm (95% CI -20.8, -8.8mm), p<0.001). Patient with US synovitis had higher rates of improvement in the MSK BILAG-2004 (56% vs. 26%, p=0.09) and SLEDAI-2K (37% vs. 15%, p=0.03).Conclusion:In lupus arthritis, distribution and serology, but not other features, help identify US-synovitis. US-synovitis was independent of features of fibromyalgia, but fibromyalgia confounded assessment of clinical response. US should be used to select SLE arthritis patients for therapy and clinical trials, especially when there are inflammatory symptoms without swollen joints.Acknowledgments:The Project was funded by Lupus-UKDisclosure of Interests:Khaled Mahmoud: None declared, Ahmed Zayat: None declared, Md Yuzaiful Md Yusof: None declared, Katherine Dutton: None declared, Lee-Suan Teh: None declared, Chee-Seng Yee: None declared, David d’cruz Grant/research support from: GlaxoSmithKline, Nora Ng: None declared, David Isenberg Consultant of: Study Investigator and Consultant to Genentech, Coziana Ciurtin Grant/research support from: Pfizer, Consultant of: Roche, Modern Biosciences, Philip G Conaghan Consultant of: AbbVie, BMS, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GSK, Novartis, Pfizer, Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer, Paul Emery Grant/research support from: AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche (all paid to employer), Consultant of: AbbVie (consultant, clinical trials, advisor), Bristol-Myers Squibb (consultant, clinical trials, advisor), Lilly (clinical trials, advisor), Merck Sharp & Dohme (consultant, clinical trials, advisor), Novartis (consultant, clinical trials, advisor), Pfizer (consultant, clinical trials, advisor), Roche (consultant, clinical trials, advisor), Samsung (clinical trials, advisor), Sandoz (clinical trials, advisor), UCB (consultant, clinical trials, advisor), Christopher Edwards Grant/research support from: Abbvie, Biogen, Roche, Consultant of: Abbvie, Samsung, Speakers bureau: Abbvie, BMS, Biogen, Celgene, Fresenius, Gilead, Janssen, Lilly, Mundipharma, Pfizer, MSD, Novartis, Roche, Samsung, Sanofi, UCB, Elizabeth Hensor: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK

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FRI0599 USEFUL II: DERIVATION OF THE LUPUS ARTHRITIS AND MUSCULOSKELETAL DISEASE ACTIVITY SCORE (LAMDA) USING DATA FROM A MULTICENTRE LONGITUDINAL STUDY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2810 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 905.2-906

Author(s):

K. Mahmoud ◽

A. Zayat ◽

M. Y. MD Yusof ◽

C. Ciurtin ◽

C. S. Yee ◽

...

Keyword(s):

Clinical Trials ◽

Disease Activity ◽

Effect Size ◽

Lasso Regression ◽

Minimal Disease Activity ◽

Research Support ◽

Becton Dickinson ◽

Tender Joint ◽

Patient Reported ◽

Minimal Disease

Background:Musculoskeletal (MSK) disease is the commonest manifestation of SLE. We showed that the MSK components of the BILAG index and SLEDAI have limited sensitivity, specificity and responsiveness compared to ultrasound (US) synovitis. The USEFUL study evaluated response to glucocorticoids in SLE patients with inflammatory pain.Objectives:To develop a disease activity tool for lupus MSK manifestations that is continuous, responsive, sensitive, and correlates with US-synovitisMethods:133 patients who received depomedrone 120mg IM were assessed at 0, 2 and 6 weeks for 66/68 swollen and tender joint counts, BILAG2004 index, SLEDAI-2K, physician global and MSK-VAS, inflammatory markers, patient pain and disease activity-VAS. Total US score (OMERACT-EULAR) in the hands and wrists was calculated blinded to patient and clinical assessor. Patients reported overall response using a Likert scale.The LAMDA was developed by modelling a core set of clinical variables against total US score using penalized (Lasso) regression. Responsiveness was compared between LAMDA and other variables at week 6 using effect sizes. Minimum clinically important difference (MCID) was explored using the SEM and minimal disease activity threshold using ROC.Results:The variables selected for the LAMDA score were swollen joint count, patient MSK pain VAS, physician MSK disease activity VAS and ESR. A continuous score was derived. This had a theoretical range from 0 to 26.5 based on maximum ESR of 100. The highest value observed in USEFUL was 15. LAMDA was significantly higher in patients with active US (mean (SD) 5.71 (2.67), n=78) compared to patients with normal US (3.27 (1.77), n=55; difference (95% CI) -2.45 (-3.26, -1.63), t=-5.93, p<0.001). This difference remained significant in patients with no swollen joints (difference (95% CI) -0.71 (-1.40, -0.02), t=-2.06, p=0.044).Effect size was greater for the LAMDA (0.37) than the BILAG-MSK (0.31), SLEDAI-MSK (0.27) and total US score (0.33). In patients with active US at baseline, LAMDA’s effect size was 0.42.The MCID was 0.71 and correlated with patient-reported change in pain. A threshold for minimal disease activity of 3.23 optimized sensitivity (0.77 (0.65, 0.89)) and specificity (0.80 (0.68, 0.92)) against US score >0.Conclusion:The LAMDA score is a novel continuous disease activity instrument for MSK manifestations of SLE derived from variables familiar to rheumatologists. The LAMDA score is sensitive to imaging detected synovitis without swelling and more responsive than other instruments. . LAMDA may improve the ability of clinicians to accurately determine therapeutic efficacy in clinical trials and practice. Future work will validate the LAMDA score in independent cohorts and randomized trials.Acknowledgements:This project was funded by Lupus UKDisclosure of Interests:Khaled Mahmoud: None declared, Ahmed Zayat: None declared, Md Yuzaiful Md Yusof: None declared, Coziana Ciurtin Grant/research support from: Pfizer, Consultant of: Roche, Modern Biosciences, Chee-Seng Yee: None declared, David Isenberg Consultant of: Study Investigator and Consultant to Genentech, Lee-Suan Teh: None declared, Katherine Dutton: None declared, David d’cruz Grant/research support from: GlaxoSmithKline, Nora Ng: None declared, Philip G Conaghan Consultant of: AbbVie, BMS, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GSK, Novartis, Pfizer, Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer, Paul Emery Grant/research support from: AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche (all paid to employer), Consultant of: AbbVie (consultant, clinical trials, advisor), Bristol-Myers Squibb (consultant, clinical trials, advisor), Lilly (clinical trials, advisor), Merck Sharp & Dohme (consultant, clinical trials, advisor), Novartis (consultant, clinical trials, advisor), Pfizer (consultant, clinical trials, advisor), Roche (consultant, clinical trials, advisor), Samsung (clinical trials, advisor), Sandoz (clinical trials, advisor), UCB (consultant, clinical trials, advisor), Christopher Edwards Grant/research support from: Abbvie, Biogen, Roche, Consultant of: Abbvie, Samsung, Speakers bureau: Abbvie, BMS, Biogen, Celgene, Fresenius, Gilead, Janssen, Lilly, Mundipharma, Pfizer, MSD, Novartis, Roche, Samsung, Sanofi, UCB, Elizabeth Hensor: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK

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Comparable Efficacy and Better Safety of Double β-Lactam Combination Therapy versus β‑Lactam plus Aminoglycoside in Gram-Negative Bacteria in Randomized, Controlled Trials

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00425-19 ◽

2019 ◽

Vol 63 (7) ◽

Cited By ~ 4

Author(s):

Yuanyuan Jiao ◽

Bartolome Moya ◽

Mong-Jen Chen ◽

Alexandre P. Zavascki ◽

Hsinyin Tsai ◽

...

Keyword(s):

Clinical Trials ◽

Clinical Response ◽

Risk Ratio ◽

Sensitivity Analyses ◽

Secondary Outcome ◽

Controlled Trials ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Content Type ◽

Randomized Controlled

ABSTRACTThere is a great need for efficacious therapies against Gram-negative bacteria. Double β-lactam combination(s) (DBL) are relatively safe, and preclinical data are promising; however, their clinical role has not been well defined. We conducted a metaanalysis of the clinical and microbiological efficacy of DBL compared to β-lactam plus aminoglycoside combinations (BLAG). PubMed, Embase, ISI Web of Knowledge, and Cochrane Controlled Trials Register database were searched through July 2018. We included randomized controlled clinical trials that compared DBL with BLAG combinations. Clinical response was used as the primary outcome and microbiological response in Gram-negative bacteria as the secondary outcome; sensitivity analyses were performed forPseudomonas aeruginosa,Klebsiellaspp., andEscherichia coli. Heterogeneity and risk of bias were assessed. Safety results were classified by systems and organs. Thirteen studies evaluated 2,771 cases for clinical response and 665 cases for microbiological response in various Gram-negative species. DBL achieved slightly, but not significantly, better clinical response (risk ratio, 1.05; 95% confidence interval [CI], 0.99 to 1.11) and microbiological response in Gram-negatives (risk ratio, 1.11; 95% CI, 0.99 to 1.25) compared with BLAG. Sensitivity analyses by pathogen showed the same trend. No significant heterogeneity across studies was found. DBL was significantly safer than BLAG regarding renal toxicity (6.6% versus 8.8%,P = 0.0338) and ototoxicity (0.7 versus 3.1%,P = 0.0137). Other adverse events were largely comparable. Overall, empirically designed DBL showed comparable clinical and microbiological responses across different Gram-negative species, and were significantly safer than BLAG. Therefore, DBL should be rationally optimized via the latest translational approaches, leveraging mechanistic insights and newer β-lactams for future evaluation in clinical trials.

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P431 Teduglutide use and nutritional outcomes in short bowel syndrome with intestinal failure: a real-world claims database analysis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.555 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S433-S434

Author(s):

D Micic ◽

J Jiang ◽

L Chen ◽

T Fan ◽

F Mu ◽

...

Keyword(s):

Sensitivity Analysis ◽

Clinical Trials ◽

Short Bowel Syndrome ◽

Real World ◽

Index Date ◽

Intestinal Failure ◽

Sensitivity Analyses ◽

Future Research ◽

Short Bowel

Abstract Background Teduglutide (TED) is a glucagon-like peptide 2 analogue approved for the treatment of patients with short bowel syndrome (SBS) requiring parenteral support (PS). SBS is a rare condition resulting from a reduced absorptive surface area of the small intestine, most commonly due to inflammatory bowel disease (IBD). Patients with SBS with intestinal failure (SBS-IF) remain dependent on PS to maintain adequate calorie, fluid, electrolyte and micronutrient stability. In phase 3 clinical trials, TED reduced PS requirements in patients with SBS-IF. This study aimed to assess PS use and discontinuation rates among patients with SBS on TED using real-world data. Methods This retrospective cohort study of adults with SBS-IF (≥18 years) with ≥1 TED pharmacy claim(s) used the US-based administrative healthcare claims IBM MarketScan database (2009–2019). The first TED claim was defined as the index date. Patients required ≥6 months of continuous enrolment prior to index date (baseline period) and no history of malignancy. Primary analysis was conducted during the follow-up period (index date to earliest of continuous enrolment end or 2 years post-index). A sensitivity analysis was also conducted among the cohort during the TED utilization period (index date to the earliest of continuous enrolment end or TED discontinuation). Patients required PS use during both baseline and follow-up/TED utilization periods (primary and sensitivity analyses). PS discontinuation was defined as a PS utilization gap of ≥30 days. A generalized estimating equation linear regression model evaluated if PS use (days/week) changed significantly from baseline to selected time points post-index. Results Of 110 identified patients with SBS-IF, mean age was 53.4 (SD 13.2) years and 77 (70%) were women. Included were 51 (46%) patients with Crohn’s disease and 20 (18%) with ulcerative colitis. The main comorbidities were renal disease (23%) and liver disease (15%). PS frequency was 4.6 (2.5), 3.3 (2.9), 2.9 (3.0) and 3.6 (3.0) days/week at baseline and months 6 (p<0.0001), 12 (p<0.0001), and 24 (p=0.0267), respectively. PS discontinuation increased over time to 34.4%, 46.7% and 65.2% at 3, 6, and 12 months, respectively. The sensitivity analysis demonstrated similar rates of PS use and discontinuation. Conclusion In this real-world study of adults with SBS-IF, including >50% with IBD, TED was associated with PS reductions comparable to those achieved in clinical trials and higher PS discontinuation rates even when using a conservative analysis approach. Future research will be required to determine individual predictive factors of PS discontinuation.

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P266 IL-4/13 inhibitor dupilumab associated with new onset peripheral axial spondyloarthritis in patients with atopic dermatitis

Rheumatology ◽

10.1093/rheumatology/keaa111.259 ◽

2020 ◽

Vol 59 (Supplement_2) ◽

Author(s):

Catherine D Hughes ◽

Bina Menon ◽

Zena Willsmore ◽

Richard Woolf ◽

Catherine Smith ◽

...

Keyword(s):

Clinical Trials ◽

Axial Spondyloarthritis ◽

Bone Erosion ◽

Human Monoclonal Antibody ◽

Power Doppler ◽

Interleukin 4 ◽

Musculoskeletal Symptoms ◽

Delayed Type Hypersensitivity ◽

Musculoskeletal Symptom ◽

Research Support

Abstract Background Dupilumab is a recombinant human monoclonal antibody that inhibits signalling of interleukin-4 and interleukin-13. It has NICE approval for use in patients with moderate to severe atopic eczema who have failed at least one standard therapy. The main reported side effects in clinical trials were allergic conjunctivitis (1-5%), injection site reactions (8-19%) and herpes viral infections (3-7%). Methods Here we report symptoms and signs of a new peripheral axial spondyloarthritis/ psoriatic arthritis type presentation in 8 patients within 16 weeks of commencing dupilumab. This has not been described previously in the clinical trials patient population. Results These patients had a long history of atopy with severe eczema and raised baseline IgE levels of > 12000. A positive response to dupilumab was seen in all patients as evidenced by marked improvements in the Eczema Area and Severity Index (EASI). Musculoskeletal symptom onset began between 2 and 16 weeks after commencement of drug. Patients typically complained of inflammatory type pain in the small joints and entheseal sites. 2/8 patients had inflammatory sounding spinal pain. Early morning stiffness was common. All patients had normal acute phase reactants and one patient had a positive rheumatoid factor. 6/8 patients had radiologically evident enthesitis as seen on MRI or ultrasound (power doppler ultrasound signal-PDUS). 3/8 patients had such severe symptoms that they had to discontinue dupilumab. All patients were commenced on non-steroidal anti inflammatories. One patient was commenced on a low dose JAK inhibitor and exhibited improvement in musculoskeletal symptoms. Conclusion IL-4 has been shown to suppress delayed type hypersensitivity reactions (DTHRs) in both human and mice studies. It has been demonstrated previously that IL-4 can prevent bone erosion and disease progression in animal models of inflammatory arthritis. Guenova et al (2015) showed that IL-4 can selectively suppress IL-23 transcription and secretion with reduced Th17 function. They suggest that administration of IL-4 may be of therapeutic benefit in Th17 mediated inflammatory conditions. Conversely, dupilumab through the inhibition of IL-4 and IL-13 and possible resultant increased IL-17 and IL-23 levels, has perhaps unmasked a tendency towards development of a peripheral axial SpA phenotype in these patients. Disclosures C.D. Hughes None. B. Menon None. Z. Willsmore None. R. Woolf None. C. Smith Grants/research support; CS is a PI/CoPI on a number of commercially supported studie (Abbvie, Janssen, Leo, Sanofi). A. Pink None. B.W. Kirkham Consultancies; BK has worked as a consultant for Eli Lilly, Gilead, Janssen and Novartis. Grants/research support; BK has received research support from Eli Lilly and Novartis.

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Stroke Prevention in Non-Valvular Atrial Fibrillation

Hämostaseologie ◽

10.1055/s-0038-1659985 ◽

1997 ◽

Vol 17 (03) ◽

pp. 166-169

Author(s):

Judith O’Brien ◽

Wendy Klittich ◽

J. Jaime Caro

Keyword(s):

Atrial Fibrillation ◽

Clinical Trials ◽

Care Home ◽

Relevant Literature ◽

Clinical Trial Data ◽

Outcome Data ◽

Sensitivity Analyses ◽

Bleeding Events ◽

Discharge Data ◽

The Cost

SummaryDespite evidence from 6 major clinical trials that warfarin effectively prevents strokes in atrial fibrillation, clinicians and health care managers may remain reluctant to support anticoagulant prophylaxis because of its perceived costs. Yet, doing nothing also has a price. To assess this, we carried out a pharmacoe-conomic analysis of warfarin use in atrial fibrillation. The course of the disease, including the occurrence of cerebral and systemic emboli, intracranial and other major bleeding events, was modeled and a meta-analysis of the clinical trials and other relevant literature was carried out to estimate the required probabilities with and without warfarin use. The cost of managing each event, including acute and subsequent care, home care equipment and MD costs, was derived by estimating the cost per resource unit, the proportion consuming each resource and the volume of use. Unit costs and volumes of use were determined from established US government databases, all charges were adjusted using cost-to-charge ratios, and a 3% discount rate was applied to costs incurred beyond the first year. The proportions of patients consuming each resource were estimated by fitting a joint distribution to the clinical trial data, stroke outcome data from a recent Swedish study and aggregate ICD-9 specific, Massachusetts discharge data. If nothing is done, 3.2% more patients will suffer serious emboli annually and the expected annual cost of managing a patient will increase by DM 2,544 (1996 German Marks), from DM 4,366 to DM 6,910. Extensive multiway sensitivity analyses revealed that the higher price of doing nothing persists except for very extreme combinations of inputs unsupported by literature or clinical standards. The price of doing nothing is thus so high, both in health and economic terms, that cost-consciousness as well as clinical considerations mandate warfarin prophylaxis in atrial fibrillation.

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PD-L1 Inhibitors for the Treatment of Prostate Cancer

Current Drug Targets ◽

10.2174/1389450121666200609142219 ◽

2020 ◽

Vol 21 (15) ◽

pp. 1558-1565

Author(s):

Matteo Santoni ◽

Francesco Massari ◽

Liang Cheng ◽

Alessia Cimadamore ◽

Marina Scarpelli ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

T Lymphocytes ◽

Chronic Inflammation ◽

Immune Cells ◽

Response To Therapy ◽

Complex Series

The carcinogenesis of prostate cancer (PCa) results from a complex series of events. Chronic inflammation and infections are crucial in this context. Infiltrating M2 type macrophages, as well as neutrophils and T lymphocytes, contribute to PCa development, progression and response to therapy. The preliminary findings on the efficacy of immunotherapy in patients with PCa were not encouraging. However, a series of studies investigating anti-PD-L1 agents such as Atezolizumab, Avelumab and Durvalumab used alone or in combination with other immunotherapies, chemotherapy or locoregional approaches are in course in this tumor. In this review, we illustrate the role of immune cells and PD-L1 expression during PCa carcinogenesis and progression, with a focus on ongoing clinical trials on anti-PD-L1 agents in this context.

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IMMU-04. IMMUNE-RELATED ADVERSE EVENTS STRONGLY PREDICT SUPERIOR OUTCOMES IN BRAIN METASTASES PATIENTS RECEIVING LOCAL TREATMENT AND IMMUNE CHECKPOINT INHIBITORS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.435 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii105-ii105

Author(s):

Alexander Hulsbergen ◽

Asad Lak ◽

Yu Tung Lo ◽

Nayan Lamba ◽

Steven Nagtegaal ◽

...

Keyword(s):

Sensitivity Analysis ◽

Adverse Events ◽

Brain Metastases ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Local Treatment ◽

Sensitivity Analyses ◽

Immortal Time Bias ◽

The Brain

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p < 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values < 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

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286. Exploratory Cost-Effectiveness Analysis for Treatment of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections: Are Daptomycin and Linezolid Favored over Vancomycin and Other Antibiotics?

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.330 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S143-S144

Author(s):

Michelle Vu ◽

Kenneth Smith ◽

Sherrie L Aspinall ◽

Cornelius J Clancy ◽

Deanna Buehrle

Keyword(s):

Staphylococcus Aureus ◽

Cost Effectiveness ◽

Methicillin Resistant Staphylococcus Aureus ◽

Bloodstream Infections ◽

Sensitivity Analyses ◽

Drug Event ◽

Base Case ◽

Health Administration ◽

Research Support ◽

Methicillin Resistant

Abstract Background Methicillin-resistant Staphylococcus aureus bloodstream infections (MRSAB) cause significant mortality and often require extended antibiotic therapy. Vancomycin, the most common initial MRSAB treatment, carries significant monitoring burden and nephrotoxicity risks. We compared cost-effectiveness of vancomycin and other antibiotic regimens as MRSAB treatment. Methods We estimated cost-effectiveness of intravenous antibiotics (vancomycin, daptomycin, linezolid, ceftaroline/daptomycin, dalbavancin) for Veterans Health Administration (VA) patients with MRSAB using an exploratory decision-tree model. Primary effectiveness outcome was composite of microbiological failure and adverse drug event (ADE)-related discontinuation at 7-days. Results In base-case analyses, linezolid and daptomycin were less expensive and had fewer treatment failures than other regimens at 4 and 6-weeks. Compared to linezolid, daptomycin incremental cost-effectiveness ratios were ~$45,000 (4-weeks) and ~$61,000 (6-weeks) per composite failure avoided, respectively. In one-way sensitivity analyses, daptomycin (4-weeks) was favored over linezolid if linezolid microbiological failure or ADE-related discontinuation rates were >14.8% (base case: 14.0%) or >14.3% (base case: 14.0%), respectively, assuming a willingness to pay (WTP) threshold of $40,000/ composite treatment failure avoided. Vancomycin was favored if its microbiological failure risk was < 16.4% (base case: 27.2%). In two-way sensitivity analyses, daptomycin was favored if linezolid microbiological failure and ADE-related discontinuation rates were >19% and > 16%, respectively. Linezolid, daptomycin and vancomycin were favored in 47%, 39%, and 11% of 4-week probabilistic iterations, respectively, at $40,000 WTP. Conclusion Daptomycin or linezolid are likely less expensive and more effective than vancomycin or other initial regimens for MRSAB. More data are needed to support safety of linezolid in MRSAB patients. Disclosures Cornelius J. Clancy, MD, Astellas (Consultant, Grant/Research Support)Cidara (Consultant, Research Grant or Support)Melinta (Grant/Research Support)Merck (Consultant, Grant/Research Support)Needham Associates (Consultant)Qpex (Consultant)Scynexis (Consultant)Shionogi (Consultant)

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EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-220884 ◽

2021 ◽

pp. annrheumdis-2021-220884

Author(s):

Kulveer Mankia ◽

Heidi J Siddle ◽

Andreas Kerschbaumer ◽

Deshire Alpizar Rodriguez ◽

Anca Irinel Catrina ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

At Risk ◽

Clinical Trials ◽

Observational Studies ◽

Task Force ◽

Musculoskeletal Symptoms ◽

Subclinical Inflammation ◽

Consensus Statements ◽

Clinical Arthritis

BackgroundDespite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA).MethodsAn European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1–10) for each PTC.ResultsEpidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants’ knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach.ConclusionThese consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.

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POS0407 PROTEOMICS ANALYSIS COMPARING THE MODE OF ACTION OF UPADACITINIB BETWEEN NON-BIOLOGIC-DMARD-IR AND BIOLOGIC-DMARD-IR PsA PATIENTS IDENTIFIES DISTINCT PATHOGENIC PATHWAYS IN THE SELECT-PsA 1 AND SELECT-PsA 2 PHASE 3 STUDIES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1652 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 433.1-433

Author(s):

T. Sornasse ◽

J. Anderson ◽

K. Kato ◽

A. Lertratanakul ◽

I. McInnes ◽

...

Keyword(s):

Disease Activity ◽

Clinical Response ◽

Rheumatic Diseases ◽

Inadequate Response ◽

Protein Biomarkers ◽

Research Support ◽

Positive Correlation ◽

Disease Biology ◽

Biologic Dmard ◽

Favorable Clinical Response

Background:Treatment of non-biologic-DMARD-IR1 (DMARD-IR) and biologic-DMARD-IR2 (bio-IR) PsA patients with upadacitinib (UPA) at 15 mg QD, an oral JAK1 selective inhibitor, resulted in significant improvement in signs and symptoms compared to placebo.Objectives:Using a pre-defined set of inflammation-related plasma protein biomarkers (pBM), to explore immunological pathway modulation by UPA 15 mg QD in PsA patients with active disease despite treatment with non-biologic or biologic DMARDs in the context of clinical response vs. non-response to treatment.Methods:Patients from the SELECT-PsA 1 (DMARD-IR) and the SELECT-PsA 2 (bio-IR) studies were randomly selected (PBO, n=100; UPA 15 mg QD, n=100 for each study). The levels of 92 inflammation related protein biomarkers (pBM) were analyzed using a multiplexed Proximity Extension Assay platform in plasma samples collected at baseline, week 2, and 12; change from baseline in protein levels was expressed as Log2 Fold Change; a Repeated Measure Mixed Linear Model was used to identify pBM modulated by UPA compared to Baseline, and those differentially modulated between responders (R) and non-responders (NR) according to ACR50, PASDAS Minimal Disease Activity, and PASI75 at week 12. Correlation of disease activity measures with relative levels of pBM were derived using Pearson’s correlation; PASI score was transformed as Log10 (x+1) prior to the analysis. Functional pathway prediction was performed in silico with a commercial distributed software.Results:At baseline, the relative levels of 37 pBM correlated with at least one baseline disease activity measure, with a marked positive correlation of IL6 with musculoskeletal end points (PASDAS and DAS28CRP), and a strong positive correlation of IL20, IL17A, IL17C, and TGFA with baseline PASI.At the single pBM-level, treatment with UPA 15 mg QD resulted in a down modulation of pBM associated with T cells, myeloid cells, and IFN-, IL6-, and TNF-related pathways in both DMARD-IR and bio-IR PsA patients. Overall effects of UPA on single pBMs were broadly similar between DMARD-IR and bio-IR patients. However, analysis of pBMs differentially modulated by UPA in R vs NR indicated that favorable clinical response (achievement of ACR50, PASDAS MDA, and PASI75) in DMARD-IR patients was associated with the down modulation of pBMs predicted to be linked to IFN, IL10, IL17, IL22, and IL27 pathways; while favorable clinical response in bio-IR patients was associated with the down modulation of multiple pBM predicted to be linked to the IL17, IL23, and IL1 pathways.Conclusion:UPA effects in both DMARD-IR and bio-IR PsA patients likely stem from the direct and indirect inhibition of multiple biological pathways belonging to the adaptive and innate immune systems. Responder/Non-Responder analysis suggests a possible shift from a TH1 biased biology in DMARD-IR PsA patients to a more TH17 biased biology in bio-IR PsA patients. This apparent change in the disease biology of PsA patients after inadequate response to prior therapy could be attributed to the actual alteration of the disease biology, treatment outcome-based patient selection, or both. Considering the clinical efficacy of UPA in both DMARD-IR and bio-IR PsA patients, this observation highlights the importance of targeting multiple pathways with drugs such as UPA for the treatment of a broad range of PsA patients.References:[1]McInnes, I. et al. Annals of the Rheumatic Diseases 79, 16-17 (2020).[2]Mease, P.J. et al.Annals of the Rheumatic Diseases, annrheumdis-2020-218870 (2020).Acknowledgements:AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.Disclosure of Interests:Thierry Sornasse Shareholder of: AbbVie, Employee of: AbbVie, Jaclyn Anderson Shareholder of: AbbVie, Employee of: AbbVie, Koji Kato Shareholder of: AbbVie, Employee of: AbbVie, Apinya Lertratanakul Shareholder of: AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Christopher T. Ritchlin Consultant of: AbbVie, Amgen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun, UCB Pharma, Grant/research support from: AbbVie, Amgen, UCB

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