NK cell subsets define sustained remission in rheumatoid arthritis.

FRI0024 HOW OFTEN DOES REACHING TARGET MISS THE MARK? LONGITUDINAL PATTERNS OF REMISSION IN REAL-WORLD EARLY RHEUMATOID ARTHRITIS PATIENTS

Anti-tumor necrosis factor (anti-TNF) antibody has revolutionized the treatment of rheumatoid arthritis (RA), and remission is now a realistic possibility for patients. Despite widespread use of anti-TNFs, predicting which patients are most likely to attain a sustained good response to these treatments remains challenging. Our objective was to undertake a systematic review of the literature to evaluate existing evidence for demographic and clinical factors associated with the achievement of sustained remission in individuals with RA treated with anti-TNF therapy. Embase, Medline, and the Cochrane Controlled Trials Register were searched along with studies identified from reference lists. Quality of studies was assessed using Newcastle-Ottawa criteria. Meta-analysis was undertaken where unadjusted odds ratios were available for the same demographic or clinical factors from at least 3 studies. Six studies were identified. Concomitant methotrexate use was associated with an increased likelihood of achieving sustained remission. Greater baseline disease activity, tender joint count, age, disease duration, baseline functional impairment, and female sex were associated with reduced likelihood of achieving sustained remission. Factors predicting sustained remission are seldom reported. Evidence identified in this review supports current recommendations for methotrexate coprescription and highlights the negative impact of particular clinical and demographic features on the likelihood of achieving optimal response to anti-TNF treatment. Sustained remission is clinically more relevant than point remission in RA. More widespread reporting of sustained remission will help clinicians set realistic expectations on likely long-term treatment efficacy and could be an important tool for identifying patients suitable for dose optimization.

The aim of this study of patients with RA in Sweden was to investigate secular trends in achieving sustained remission (SR), i.e. DAS28 <2.6 on at least two consecutive occasions and lasting for at least 6 months. All adult RA patients registered in the Swedish Rheumatology Quality register through 2012, with at least three registered visits were eligible, a total of 29 084 patients. Year of symptom onset ranged from 1955, but for parts of the analysis only patients with symptom onset between 1994 and 2009 were studied. In total, 95% of patients fulfilled the ACR 1987 classification criteria for RA. Odds of reaching SR for each decade compared with the one before were calculated with logistic regression and individual years of symptom onset were compared with life table analysis. Of patients with symptom onset in the 1980s, 1990s and 2000s, 35.0, 43.0 and 45.6% reached SR, respectively (P < 0.001 for each increment), and the odds of SR were higher in every decade compared with the one before. The hazard ratio for reaching SR was 1.15 (95% CI 1.14, 1.15) for each year from 1994 to 2009 compared with the year before. Five years after symptom onset in 2009, 45.3% of patients had reached SR compared with 15.9% in 1999. There is a clear secular trend towards increased incidence of SR in patients with RA in Sweden. This trend most likely reflects earlier diagnosis and treatment start, and adherence to national and international guidelines recommending the treat to target approach.

SAT0040 Prevalence and Predictors for Sustained Remission in Rheumatoid Arthritis

AB0144 PREDICTIVE FACTORS OF SUSTAINED CLINICAL REMISSION IN RHEUMATOID ARTHRITIS

Our study was aimed at investigating dynamic phenotype pattern of peripheral blood NK cells in patients with widespread purulent peritonitis (WPP) during postoperative period depending on disease outcome. A total of 48 patients aged 30–63 with acute surgical diseases and abdominal injuries complicated by WPP were examined. Blood sampling was performed before surgery (preoperative period) as well as on day 7, 14 and 21 during postoperative period. 40 apparently healthy age-matched subjects were included in control group. Peripheral blood NK cell phenotyping was performed by using flow cytometry with directly immunofluorescently tagged antibodies. Mean fluorescence intensity was measured to estimate expression levels of NK cell surface receptors was measured. It was found that in patients with a favorable WPP outcome during preoperative period the percentage of mature NK cells was decreased that was restored by the end of the postoperative period (21 days post-surgery) due to elevated mature, cytotoxic and cytokine-producing NK cell subsets. In addition, percentage of CD11b-positive NK cell subsets was increased upon favorable outcome by the end of postoperative period as well as frequency of CD57-positive NK cells relative to the preoperative period. However, frequency of mature NK cells with unfavorable WPP outcome vs. control vs. favorable outcome was decreased during preoperative and entire postoperative period. Moreover, amount of cytotoxic NK cells was elevated during examination period upon unfavorable WPP outcome. Further, percentage of mature CD11b-positive NK cells in this patient cohort was decreased during preoperative period and post-surgery. Percentage of CD57-positive NK cells was decreased during entire postoperative period in patients with unfavorable vs. favorable outcome vs. control group. At the same time, patients with unfavorable outcome of this infectious-inflammatory disease were shown to display upregulated expression of CD28 and CD57 markers on NK cells. such features identified in phenotype of peripheral blood NK cells in patients with unfavorable WPP outcome reflect abnormal mechanisms in NK cell maturation and migration, which, in turn, determines disturbance in events regulating acute inflammatory reaction in WPP.

To investigate the prevalence and predictors of sustained remission (SR) in an unselected Chinese rheumatoid arthritis (RA) population. Medical records of RA patients from 2009 to 2016 were retrospectively reviewed. Clinical remission was defined according to Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and Boolean criteria. Remission persisting for at least 6months was regarded as SR (6-month SR). Kaplan-Meier method and Cox regression analyses were performed to plot cumulative possibility of achieving 6-month SR and to identify predictors. Seven hundred and seventy-nine patients contributing 7958 clinic visits were included. During the follow-up period, nearly half of patients achieved 6-month SR according to DAS28-ESR (51.6%), CDAI (45.6%), SDAI (44.0%), as well as Boolean definitions (42.4%). Median time periods to 6-month SR were respectively 20.5, 28.7, 30.6, and 32.9months based on the above criteria. Specifically, 29.4% to 41.2% of patients achieved 6-month SR at least once in the first year of follow-up, depending on instruments. Multivariate Cox regression indicated that increasing age, longer disease duration, higher baseline disease activity were independently correlated with reduced possibility of 6-month SR assessed by nearly all definitions. Conversely, male, early RA, disease-modifying antirheumatic drug-naïve and lower disease activity scores in remission measured by corresponding criteria positively contributed to SR. Importantly, treat-to-target (T2T) adherence therapy and shorter time to remission were identified as stable determinants of SR across all definitions. Achieving 6-month SR was not uncommon in daily practice. Male, early RA, treatment-naïve, T2T application, shorter time to remission, and lower disease activity scores in remission increased the occurrence of SR, while increasing age, longer disease duration, and higher baseline disease activity reduced the chance of remission sustainability.

Natural killer (NK) cells are innate immune cells with the ability to kill tumor cells without prior exposure. NK cells express multiple activating and inhibitory receptors in addition to the low-affinity immunoglobulin G binding receptor CD16. Accumulating evidence implicates a role of NK cells in not only direct killing of tumor cells, but also in cancer immunosurveillance and preventing metastasis to tissues sites. However, at present the distribution, diversity and tissue driven differences in NK cell function are not well characterized which may have an implication on the anti-cancer potential of tissue NK cells. Through collaboration with LiveOnNY our local organ procurement organization, we receive blood, bone marrow (BM), lung, intestines, tonsil and associated lymph nodes (LN) from research consented organ donors. Here we used this unique tissue resource to investigate the distribution, phenotypic, functional and transcriptional diversity of NK cell subsets in human tissues. We found that NK cells are ubiquitously distributed in human tissues comprising up to 40% of the CD45+ CD14/19- cells in blood, BM, spleen and lung, while only a small fraction (up to 2%) in the intestine and the LN. While blood, BM, spleen and lung are dominated by mature NK cells (CD56dim CD16+), majority of the NK cells in intestine and LN are immature (CD56hi CD16-). Age, sex and CMV sero-status do not show any correlation with NK cell distribution or subset frequency in tissues. Notably, NK cell subset distribution seems to drive functional differences between tissue NK cells, with lymphoid site NK cells expressing lower levels of effector molecules granzyme B, TNFα, Prf, Ifnγ and displaying reduced degranulation compared with their counterparts from blood, BM and spleen. For an in-depth analysis of tissue-mediated effects on NK cell subset functionality, we performed whole-transcriptome profiling on immature and mature NK cells isolated from blood, BM, spleen, lung and LN. Our analysis identified several effector molecules and NK cell surface receptors being differentially expressed between immature and mature NK cells. Furthermore, while mature NK cells of blood and tissues have similar transcriptional profiles, the transcriptional profiles of immature blood and tissue NK cells show tissue driven heterogeneity with differential expression of transcription factors, metabolic enzymes and NK cell surface receptors. Interestingly, the transcriptional signature of immature NK cells is reminiscent of the transcriptional signature of tissue resident memory T-cells showing increased expression of CD103, CD49a, CXCR6. We validated the expression of these markers using multiparameter flow cytometry and found that subset of immature NK cells in mucosal sites (lung and intestine) do indeed express markers of tissue residence. Additionally, by applying trajectory projection algorithm on NK cells from tissue sites, we show that resident NK cells comprise a distinct population from immature NK cells. Our study has identified novel, previously unidentified diversity of tissue NK cells. Phenotypic and transcriptional profiling data provide evidence for putative resident NK cells being present in certain tissue sites. Blood NK cells differ from their counterparts in tissues; especially, immature NK cells in tissues may be specifically trained to function in the tissue environment. Finally, due to the uniqueness of phenotypic, functional and transcriptional features of tissue NK cells, they may be more suited to fight cancer in situ in tissues. Citation Format: Pranay Dogra, Takashi Senda, Peter Szabo, Dustin Carpenter, Marta Toth, Puspa Thapa, Mark Snyder, Michelle Miron, Brahma Kumar, Donna L. Farber. Human NK cell distribution memory and residence in tissue sites [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B153.

BackgroundNatural killer (NK) cells are innate immune cells that generate inflammatory responses important for anti-tumor responses. NK cell therapies have been increasingly explored and tested as a novel approach to...

Background: Despite advances in pharmacologic management, achieving sustained remission in rheumatoid arthritis (RA) remains challenging, particularly among patients who exhibit suboptimal responses to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate (MTX). The emergence of targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), including Janus kinase (JAK) inhibitors, has expanded therapeutic options by directly modulating intracellular signaling pathways central to inflammation and immune activation. Among these, tofacitinib has demonstrated efficacy in clinical trials, yet its real-world performance, safety profile, and predictors of treatment response are less clearly defined. Real-world data, reflecting diverse patient populations and routine clinical practice, are essential for complementing randomized controlled trials (RCTs) and for guiding evidence-based, individualized treatment strategies in RA management.Methods: This retrospective real-world study included 450 RA patients treated with tofacitinib following MTX failure. Demographics, clinical characteristics, laboratory results, treatment history, and comorbidities were assessed. Outcomes included changes in disease activity score 28 (DAS28), Health Assessment Questionnaire (HAQ), pain, and stiffness at six months, along with adverse event monitoring. Exploratory data analysis and machine learning models (logistic regression, random forest, XGBoost, LightGBM, and support vector machine {SVM}) were applied to predict treatment response.Results: The mean age was 51.2±12.4 years, with 236 females (52.4%). At six months, DAS28 decreased significantly (5.4±1.1-3.2±1.0; p<0.001), with 286 patients (63.6%) achieving low disease activity and 142 patients (31.6%) reaching remission. HAQ improved from 1.5±0.6 to 0.9±0.5 (p<0.001). Adverse events occurred in 132 patients (29.3%), mostly mild infections. Machine learning models identified CRP, disease duration, and baseline DAS28 as key predictors; however, the predictive performance for treatment response was generally limited, with most models showing area under the curve (AUC) values below 0.65.Conclusion: Tofacitinib demonstrated significant clinical benefit in RA patients with inadequate MTX response, with acceptable safety. While machine learning highlighted key predictors, future work with larger datasets is needed to optimize predictive accuracy and personalize therapy.

AB0144 The expression of NKG2D ligands in synovial cell of rhuematoid arhtirits

Combined Genetic Ablation of CD54 and CD58 in CAR Engineered Cytotoxic Lymphocytes Effectively Averts Allogeneic Immune Cell Rejection

Objective assessment of the remission state and Predictors of sustained Remission in Rheumatoid Arthritis: leading to development of new management guidelines

SAT0747-HPR Can achieving sustained das remission prevent progression of sub- clinical atherosclerosis? a prospective cohort study in early rheumatoid arthritis (ERA)

&lt;p&gt;Supplementary Figure 1. Dose response in Treg and NK cell subsets upon WT IL-2 or F42K stimulation Supplementary Figure 2. Gating strategy for Tregs upon WT IL-2 or F42K stimulation Supplementary Figure 3. CD127 expression by ICOS+ Tregs and CD4+Foxp3- effector T cells Supplementary Figure 4. KI67 expression by NK cells after WT IL-2 or F42K stimulation Supplementary Figure 5. Effect of IL-2 mutant on purified cell populations Supplementary Figure 6. NK cell phenotype 3 days after WT IL-2 or F42K stimulation Supplementary Figure 7. Expression of activation markers by NK cells 6 days after WT IL-2 or F42K stimulation Supplementary Figure 8. Expression of inhibitory molecules by NK cell after WT IL-2 or F42K stimulation Supplementary Figure 9. Expression of cytolytic mediators by NK cells 6 days after WT IL-2 or F42K stimulation Supplementary Figure 10. IL-2 serum level post hydrodynamic gene transfer in mouse model Supplementary Figure 11. Changes of ICOS+ Tregs and NK cells in mouse model Supplementary Table 1. Immune response-related genes differentially regulated in F42K to WT IL-2&lt;/p&gt;