tbuckley/cabot-search huggingface dataset:
AB1735 TRANSLATION AND VALIDATION IN ITALIAN OF THE METHOTREXATE INTOLERANCE SEVERITY SCORE FOR CHILDREN AND ADULTS WITH ARTHRITIS
Authors: G. Tarantino, R. Nicolai, A. Aquilani, A. Tomasini, A. Celano, S. Magni-Manzoni, F. De Benedetti, E. Marasco
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Methotrexate (MTX) is the most used drug for the treatment of children and adults suffering from arthritis although its intake is burdened by well-known side effects. The Methotrexate Intolerance Severity Score (MISS) was originally developed in English [1] to identify patients intolerant to MTX. <h3>Objectives:</h3> Methotrexate (MTX) is the most used drug to treat children and adults with arthritis and its use is burdened by adverse effects. The MTX intolerance severity score (MISS) was developed in English to identify patients who are intolerant to MTX. The aim of this study was to translate and validate the MISS in Italian. <h3>Methods:</h3> The Italian version of the MISS was developed following the "guidelines for process of cross-cultural adaptation of self-reported measures". The Italian version of the MISS was validated in 125 patients with juvenile idiopathic arthritis (JIA) followed at the Rheumatology Unit of Bambino Gesù Children Hospital. We assessed the construct validity and calculated the internal consistency of the Italian MISS. We performed ROC analysis to assess the overall performance of the Italian MISS. <h3>Results:</h3> Of the study cohort (83% female), 71 patients had oligoarthritis, 43 had RF-negative polyarthritis, 4 had enthesitis-related arthritis (ERA), and 3 had psoriatic arthritis. The mean age (±IQR) at diagnosis was approximately 4 years, with a "disease duration" on the MISS questionnaire of 6 years (IQR 3.3-10.5). The mean (± SD) VAS and c-JADAS scores were 0.7 and 2.4 respectively, with 65% of patients having inactive disease. The majority (98%) of patients received MTX subcutaneously and the average duration of use of the drug was approximately 5 years. We translated and adapted the MISS to the Italian language. The Italian MISS showed a very good internal consistency as shown by a Cronbach a of 0.87 (95% CI, 0.84-0.90) and a composite reliability of 0.89 (95% CI, 0.83-0.91). A threshold of 6 to define intolerant patients, showed a sensitivity of 98.3% and specificity of 81.2%. <h3>Conclusion:</h3> We developed the Italian version of the MISS and showed its validity and reliability to identify patients intolerant to MTX in clinical practice and in a research setting. <h3>REFERENCES:</h3> [1] M. Bulatović et al., "High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: development and validation of a methotrexate intolerance severity score." Arthritis Rheum 63, 2007-2013 (2011). [2] D. Wild et al., "Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: report of the ISPOR Task Force for Translation and Cultural Adaptation." Value Health 8, 94-104 (2005). <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
AB1611-HPR ADAPTED PHYSICAL ACTIVITY IN THE PRACTICE OF MOROCCAN RHEUMATOLOGISTS: A MULTICENTER NATIONAL SURVEY
Authors: F. Kronbi, H. Rkain, N. Benzine, S. Ez-Zaoui, R. Honsali, I. Bensaghir, H. L ’heri, S. Farih, T. Latifa, N. Hajjaj-Hassouni, F. Allali
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Increasing physical activity and decreasing sedentary behaviors are major therapeutic interventions in inflammatory rheumatic diseases (IRD). Interventions targeting physical activity and sedentary behaviors can contribute to decrease pain, improve function and quality of life [1]. <h3>Objectives:</h3> The objective of this study is to collect the perceptions and practices of Moroccan rheumatologists regarding the integration of adapted physical activity (APA) in the management of chronic inflammatory rheumatism (CIR) and analyze the factors associated with this integration. <h3>Methods:</h3> It is a descriptive and analytical cross-sectional study conducted among the community of Moroccan rheumatologists. 440 rheumatologists received a Google Forms questionnaire consisting of 16 questions divided into 3 sections: Sociodemographic data of Moroccan rheumatologists, their perceptions regarding the role of adapted physical activity (APA) in the non-pharmacological management of chronic inflammatory rheumatism (CIR), and their practices. A Likert scale ranging from 1 to 5 was used to respond to the questions. <h3>Results:</h3> Among the 440 contacted rheumatologists, 132 rheumatologists (mean age of 44 ±12 years, 84.8% female, average years of practice 15.4 ± 12) responded to the survey (response rate of 30%). Rheumatologists consider that adapted physical activity (APA) is an integral part of the non-pharmacological management of chronic inflammatory rheumatism (CIR) in % of cases. The modalities of the integration of APA into the practice of Moroccan rheumatologists are presented in Table 1. No factor among the socio-demographic characteristics related to rheumatologists was significantly associated with the integration of Adapted Physical Activity (APA) in the management of Inflammatory Rheumatic Diseases (RIC) by Moroccan rheumatologists. <h3>Conclusion:</h3> This work provides an overall overview of the integration of adapted physical activity (APA) in the practice of Moroccan rheumatologists, which appears to be quite satisfactory. Nevertheless, it would be interesting to focus on raising awareness and training rheumatologists on the dispensing methods of APA programs to be adopted in the management of chronic inflammatory rheumatism (CIR). <h3>REFERENCES:</h3> [1] Julie Soulard et al. Physical activity in inflammatory rheumatic disorders: Health trajectories and promotion of physical activity. Revue du Rhumatisme, May 2023 Volume 90, Issue 3, Pages 334-345. <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
POS1397 NEUTROPHIL-DERIVED LAMP1 IS ASSOCIATED WITH PROLIFERATIVE LUPUS NEPHRITIS
Authors: R. Grieshaber-Bouyer, P. Garantziotis, L. Ostendorf, J. Schoen, G. Schett, D. Rao
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Defining useful molecular features of Systemic Lupus Erythematosus (SLE) heterogeneity remains a major challenge. Identifying blood and urine biomarkers associated with lupus nephritis could unlock non-invasive diagnosis and monitoring. <h3>Objectives:</h3> We investigated cellular and molecular parameters associated with the clinical heterogeneity of SLE patients with lupus nephritis. <h3>Methods:</h3> Mass cytometry data of blood leukocytes was analyzed from patients with biopsy confirmed lupus nephritis and compared to healthy controls. Proteomics and ELISA were performed to analyze urine proteins and LAMP1 levels in serum, respectively. Flow cytometry and confocal microscopy were used to analyze the distribution of LAMP1 in neutrophils under steady state and after activation. <h3>Results:</h3> Patients with lupus nephritis displayed increased expression of the degranulation marker LAMP1 in blood leukocytes compared to healthy blood donors. This increase was due to an expansion of neutrophils expressing LAMP1, and neutrophils displayed higher LAMP1 levels than other leukocytes. Neutrophil phenotypes appeared to mark an independent axis of SLE heterogeneity, as the proportion of LAMP1+ neutrophils showed no correlation with frequencies of T peripheral helper cells, T follicular helper cells and age associated B cells. LAMP1 expression showed an association with proliferative (class III/IV) lupus nephritis. Flow cytometry confirmed the presence of LAMP1+ patients in the blood of SLE patients but not healthy donors. Intracellular staining revealed that resting blood neutrophils of healthy donors contained LAMP1 intracellularly but did not express it on their surface. Confocal microscopy confirmed the intracellular localization of LAMP1 in lysosomes and secretory vesicles. Activation with fMLP lead to externalization and an increase in LAMP1 on the surface of neutrophils. In serum, soluble LAMP1 could be detected by ELISA and concentrations were higher in SLE patients compared to healthy controls. Specifically, patients with proliferative (class III/IV) lupus nephritis had the highest levels of serum LAMP1. LAMP1 was also detectable in urine and the highest levels were again observed in patients with proliferative lupus nephritis. <h3>Conclusion:</h3> These data demonstrate that neutrophil phenotypes can define a novel axis of lupus heterogeneity and nominate neutrophil-derived LAMP1 as marker for proliferative lupus nephritis. Thus, molecular profiling of blood and urine may have utility for non-invasive diagnostics and monitoring of lupus nephritis. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
Updated efficacy and safety results of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).
Authors: Masa Lasica, Sikander Ailawadhi, Chengcheng Fu, Sheeba K. Thomas, Depei Wu, Shuhua Yi, Tanya Siddiqi, Qingsong Yin, John N. Allan, Wenming Chen, Jeffrey V Matous, Ru Feng, Zi Chen, Min Yu, Mingyu Li, Zicong He, Mohammad Ahmad, Hengbang Wang, Asher Alban Akmal Chanan-Khan, Yifan Zhai
Journal: Journal of Clinical Oncology (2024)

7078 Background: Lisaftoclax is a novel, oral, highly selective, potent BCL-2 inhibitor in development. In an ibrutinib-resistant patient-derived WM xenograft/preclinical model, lisaftoclax + ibrutinib has a strong synergistic effect. This report provides updated efficacy and safety data of lisaftoclax-based therapies (including combinations with ibrutinib) in pts with WM. Methods: In this global, open-label, phase 1b/2 multicenter study, pts with WM were enrolled in 3 arms: Arm A (lisaftoclax) included BTKi-resistant/intolerant pts; Arm B (lisaftoclax + ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax + rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high risk of tumor lysis syndrome (TLS). Objectives were efficacy, safety, and pharmacokinetics (PK) assessments (responses assessed per IWWM criteria). Results: As of January 25, 2024, 46 pts were enrolled and treated at doses of up to 1,000 (Arm A), 1,200 (Arm B), and 800 mg (Arm C; Table). The median (range) treatment duration was 11 (1-28; Arm A), 23.5 (1-34; B), and 11.5 (5-33; C) months. Objective response rates (PR, VGFR, CR) were: 41.7% (Arm A), 90.9% (B), and 37.5% (C). In Arm A, pts with wild-type CXCR4 (n = 7) had better overall response to lisaftoclax than the CXCR4 mut group (n = 3). No significant difference was observed between pts with/without CXCR4 mut in Arms B and C. In Arm B, 1 DLT (grade 3 clinical TLS due to preexisting renal impairment) was reported at 1,200 mg; 1 grade 3 laboratory TLS, primarily attributed to dehydration and concomitant symptomatic therapies, occurred at 1,000 mg; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (15.2%), thrombocytopenia (4.3%), decreased leukocytes (4.3%), TLS (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmia was not observed. One pt required dose reduction because of neutropenia. The MTD was not reached. Lisaftoclax + ibrutinib showed a PK exposure comparable to lisaftoclax or ibrutinib alone, indicating no potential drug-drug interactions. Conclusions: Lisaftoclax alone and combined with ibrutinib or rituximab was well tolerated and demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. (CT.gov: NCT04260217; Internal ID: APG2575WU101) *Co-first authors: ML and SA. Clinical trial information: NCT04260217 . [Table: see text]
Phase 1b trial of IRAK 1/4 inhibition for low-risk myelodysplastic syndrome refractory/resistant to prior therapies.
Authors: Guillermo Garcia-Manero, Lewis R. Silverman, Mikkael A. Sekeres, Lucy Yan
Journal: Journal of Clinical Oncology (2024)

TPS6591 Background: Chronic stimulation of both the interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to promote a proinflammatory environment in the bone marrow that causes persistent cytopenia in patients with low-risk myelodysplastic syndrome (LR-MDS). The serine/threonine kinases IRAK1 and IRAK4 are critical for the signaling downstream of IL-1R and most TLRs promote production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis, leading to bone marrow inflammation and cell death. IRAK1/4 is a potential target for inhibition for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow, allowing for restoration of hematopoiesis. R289 is a prodrug for R835, a potent and selective inhibitor of IRAK1 and IRAK4 kinases. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 study in healthy volunteers (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the study supported the further evaluation of R289. An open-label, phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently enrolling patients. Methods: The R289 phase 1b open label, single arm, multi-center study (NCT05308264) includes a dose escalation phase (up to 24 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases: patients ≥18 years with a definitive diagnosis of LR-MDS. Exclusion criteria include prior MDS treatment(s) within 4 weeks of study treatment. Dose Escalation Phase: A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD). An initial R289 dose of 250 mg qd, will be given orally, with or without food, progressing to 1 g qd with dose limiting toxicity (DLT) assessed at each dose level. The DLT evaluation period will be 28 days. After completion, patients without DLTs may remain at their respective dose levels if clinical benefit continues without toxicity. Dose Expansion Phase: R289 will be administered to up to 10 additional patients with LR-MDS at a dose not exceeding the MTD in the dose escalation phase. The primary endpoint is safety and tolerability of R289. Secondary endpoints include preliminary efficacy and pharmacokinetics of R289. Statistical analyses will be primarily descriptive. The trial is currently ongoing at 9 US sites. Clinical trial information: NCT05308264 .
A retrospective observational study of rapid titration of venetoclax (VEN) in patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).
Authors: Tijesuni Babalola, Emily C. Ayers, Michael G. Douvas, Laahn Foster, John Densmore, Michael E. Williams, Craig Anthony Portell
Journal: Journal of Clinical Oncology (2024)

e19018 Background: CLL and MCL can present with rapid disease progression that requires quick control. VEN is an oral, small-molecule inhibitor of BCL-2 that requires careful dose titration to avoid TLS. However, standard outpatient titration of VEN takes 29 days to reach max dose, with the low doses achieving little disease control. A common practice at our site is to rapidly titrate VEN to 100mg within 1 week with hospitalization for careful TLS monitoring and management. We present the safety and outcomes of 39 identified patients treated as such. Methods: The rapid VEN titration plan was: VEN 20mg x 2 days, 50mg x 2 days, then 100mg daily with q6-q8 hour monitoring of TLS labs plus ongoing IV hydration and allopurinol with or without rasburicase per clinical judgment. Most patients were treated in such manner if TLS did not occur. Clinically stable patients were typically discharged after 2 days of VEN 100mg, then continued weekly outpatient dose escalation to the 200mg and then the 400mg dose levels. If a patient was progressing on a Bruton's Tyrosine Kinase inhibitor, the inhibitor was often given concurrently with the early doses of VEN. Results: Patient characteristics are listed in the table. 23% (5 of 22) of patients with CLL and 35% (6 of 17) of patients with MCL had laboratory TLS (Howard SC, NEJM2011). In the patients with CLL, 2/5 were low risk for TLS, and in the patients with MCL, 3/6 were low risk for TLS. Only 4.5% (1 of 22) of CLL patients and no MCL patients had clinical TLS (Grade 2 creatinine elevation). In that specific patient, considered low risk for TLS, the elevated creatinine did not recover but was subsequently deemed secondary to Richter’s transformation involving the kidneys. No unexpected toxicity was observed outside of those typically associated with VEN and anti-CD20 antibody, when used. The mean number of days to reach 100mg was 6.5 days (quartile [Q] 1:5d; Q3: 10d), and the mean number of days to reach the planned VEN target dose was 18.8 with range (Q1:14d; Q3: 25d). Sixty-four percent of patients achieved the 400mg dose level. Conclusions: This single-institution retrospective analysis highlights the low rate of clinical TLS when using VEN with rapid titration in a controlled environment for high-risk patients needing rapid disease control. However, lab TLS occurred in low-risk patients treated in this manner, necessitating hospitalization despite low risk. No unexpected or additional toxicity was observed. [Table: see text]
POS1015 SHARED DECISION-MAKING ENHANCES TRUST IN PHYSICIANS IN THE CLINICAL PRACTICE OF SYSTEMIC LUPUS ERYTHEMATOSUS: THE TRUMP2-SLE PROSPECTIVE STUDY
Authors: R. Yoshimi, N. Yajima, C. Hidekawa, N. Sakurai, N. Oguro, K. Shidahara, K. Hayashi, T. Ichikawa, D. Kishida, Y. Miyawaki, K. E. Sada, Y. Shimojima, Y. Ishikawa, Y. Yoshioka, Y. Kunishita, D. Kishimoto, K. Takase-Minegishi, Y. Kirino, S. Ohno, N. Kurita, H. Nakajima
Journal: Annals of the Rheumatic Diseases (2024)
AB1634-HPR COMPETENCIES AND CHALLENGES IN RHEUMATOLOGISTS’ TRAINING: AN ANALYSIS OF ADHERENCE TO EULAR GUIDELINES
Authors: L. Sorrentino, G. Gómez, J. A. Brigante
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> In 2023, the EULAR group published a series of points to consider in the training of rheumatologists. This study aims to expand its scope to understand the educational landscape in rheumatology in Argentina. <h3>Methods:</h3> The study population consisted of rheumatologists selected through a sampling approach. For data collection, a structured questionnaire was designed using the Google Forms platform. The questionnaire construction adhered rigorously to the guidelines provided by the "EULAR Points to Consider: EULAR–UEMS standards for the training of European rheumatologists" guide. The questions aimed to assess participants' confidence in each competency upon completing their training. <h3>Results:</h3> A total of 46 participants were included. The median age was 40 years, ranging from 31 to 79 years, with training spanning from 1976 to 2023. Regarding education, 71.7% received their training in public institutions. The majority of respondents (82.6%) were trained in the City of Buenos Aires, followed by the Province of Buenos Aires, Santa Fe, Mendoza and Córdoba. Overall, surveyed rheumatologists expressed a high level of confidence in their clinical skills and competencies upon completing their training. However, when specifically asked about metabolic bone diseases, 26% responded neutrally, and 7% did not feel competent. A similar pattern was observed in managing diseases based on age groups, with 26% being neutral, and 9% and 4% in disagreement and total disagreement with feeling competent. 10.9% were neutral, and 6.5% disagreed regarding their ability to manage diseases in the context of multimorbidity. 13% disagreed, and 26% were neutral about their ability to manage rheumatological pathologies during pregnancy and lactation. Regarding generalized pain syndromes, 80% felt competent, while 4% disagreed, and 15% were neutral. In aspects related to ethics and communication, most participants felt capable of establishing professional relationships based on mutual trust and respect (45.7%), as well as effectively communicating with patients and other healthcare professionals (39.1%). <h3>Conclusion:</h3> The results reflect a group of rheumatologists who perceive themselves as competent in a wide range of clinical and ethical skills upon completing their training. However, it is important to note that, despite the high perception of competence, self-assessment may vary, and ongoing education may be beneficial to maintain and enhance these skills throughout their professional careers. <h3>REFERENCES:</h3> [1] Alunno, Alessia, et al. "Points to consider: EULAR–UEMS standards for the training of European rheumatologists." Annals of the Rheumatic Diseases (2023). <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>