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BackgroundEarlier studies, before the era of biologics, showed that rheumatoid arthritis (RA) patients were at higher risk of overall malignancies, with an excess relative risk of 28% compared to the general population. This risk is mostly carried by specific cancers such as lung cancer, lymphomas along with skin cancers. An update of cancer incidence is warranted in order to explore whether cancer risk has been modified in the era of biological and targeted DMARDs.ObjectivesTo estimate the risk of cancer in patients with rheumatoid arthritis compared to the general population.MethodsWe conducted a nationwide population-based study within the French national claim database “Système National des Données de Santé” (SNDS) between January 1st 2010 and December 31st 2020. We estimated the age and sex-standardized incidence ratios (SIR) and [95% CI] of cancer (all sites, site specific and hematologic malignancies) of RA patients, with the French population as reference, by use of the French Network of Population-Based Cancer Registries (FRANCIM). SIR were estimated with Poisson regression models.ResultsDuring the study period, 257,075 patients met the eligibility criteria, who contributed to a total of 1,906,742 person-years for the main analysis. RA patients had an increased risk of overall malignancy (SIR 1.20 [1.17-1.23]), particularly lung (SIR 1.41 [1.36-1.46], bladder (SIR 2.38 [2.25-2.51]), ears-nose-throat (SIR 1.40 [1.31-1.50]), cervix (SIR 1.80 [1.62-2.01]), prostate (SIR 1.08 [1.04, 1.13]), melanoma (SIR 1.37 [1.29-1.46]) cancers, marginal zone (SIR 1.22 [1.06-1.42]), diffuse large b cell (SIR 1.79 [1.63-1.96]), and Hodgkin (SIR 2.68 [2.23-3.18]) lymphomas, and multiple myeloma (SIR 1.50 [1.36-1.65]). Of note, some cancers were less frequent than in the general population such as pancreatic cancer (SIR 0.90, [0.83-0.97]) as well as breast and uterine body cancers (SIR 0.91 [0.88-0.94] and SIR 0.77 [0.71-0.84] respectively). Subgroup analyses revealed that the risk of overall malignancy was significantly less increased in women (SIR 1.08 [1.06-1.10]) than in men (SIR 1.34 [1.31-1.36]) (between group difference p < 0.001). Whereas, the risk of pancreatic cancer was only decreased in men but not in women (SIR 0.83 [0.75-0.91] vs SIR 1.04 [0.92-1.17] respectively, p < 0.001). Full details are presented in the Figure 1 below.Overall risk of cancer was increased in patients treated with csDMARD (SIR 1.15 [1.13-1.17]), Tumor Necrosis Factor inhibitors (SIR 1.11, [1.07-1.15]), abatacept (SIR 1.27 [1.16-1.39]) and rituximab (SIR 1.43 [1.31-1.55]) versus the general population, however this association was not found in patients exposed to anti-IL6 (SIR 1.00 [0.90-1.10]) and Janus Kinase inhibitors (SIR 0.97 [0.77-1.21]).ConclusionIn the era of biologics, RA patients remain at greater risk of overall malignancy and some site-specific cancers, not only lung cancer and lymphoma. This higher incidence of overall malignancy was observed in RA patients treated with almost all type of DMARD or bDMARD. However, no causal relationship between treatments and cancer incidence can be drawn as indication bias was not taken into account. Of note, we observed a lower incidence of breast, pancreatic and uterine body cancers than the general population.ReferencesNIL.Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background:Sjögren disease (SjD) is the autoimmune disease with the highest risk of lymphoma. The most common histology is marginal zone (MZ) lymphoma particularly the mucosa-associated lymphoid tissue (MALT) lymphoma. There is a continuum between autoimmunity and lymphoma, and disease activity is a major risk factor for lymphoma development. Managing lymphoma complicating SjD remains non-consensual with different options: wait and watch, local or systemic therapy.Objectives:To describe characteristics of non-Hodgkin lymphoma in Sjögren disease (SjD), therapeutic strategies, and the impact of these strategies on the prognosis of lymphoma and SjD.Methods:This multicentric retrospective study included all lymphoma patients of the ASSESS prospective cohort, enriched with patients recruited in 15 French Rheumatology and Internal Medicine departments. We collected biological and clinical manifestations of SjD, lymphoma characteristics, and treatment strategy. Exploratory analysis identified factors associated with lymphoma relapse, SjD relapse and overall survival (OS). Propensity scores were created using key clinical variables to compare patients depending on treatment strategy. Three outcomes were analyzed: lymphoma progression-free survival (Lymphoma-PFS), Sjögren Disease progression-free survival (SjD-PFS), and OS.Results:One hundred and six patients were included. The most frequent histological subtype was MZ lymphoma (82 patients) including 68 MALT, followed by 14 diffuse large B cell lymphoma.Among the 82 patients with MZ lymphoma, after multivariate adjustment on age, localization, Bendamustine use, Ann arbor stage and calendar year at lymphoma diagnosis, older age and pulmonary involvement were negatively associated with overall survival (HR 1.15 CI 95% [1.05-1.26] and HR 6.40 CI 95% [1.10-37.1]). We did not find individual factors associated with lymphoma or SjD-PFS. Fifty (61%) MZ patients received systemic treatment with chemotherapy and/or rituximab. These patients had more frequently pulmonary lymphoma locations (24% vs 3.1%, p = 0.012) and tended to have higher SjD disease activity at lymphoma diagnosis. After a median follow-up of 7 years, 26 patients (32%) experienced lymphoma relapse, 9 (11%) died, and 27 (33%) experienced SjD relapse. After propensity score adjustment, patients treated with first line systemic treatments for lymphoma, displayed a longer SjD progression-free survival (PFS) (HR=0.43 [95% CI 0.21-0.90], p = 0.026) than patients without systemic treatment (including watch and wait strategy or local treatment alone). There was no difference in lymphoma relapse nor overall survival. Patients treated with first-line combo-therapy (anti-CD20 and chemotherapy) had a longer lymphoma-PFS than patients with first-line monotherapy (anti-CD20 or chemotherapy): HR 0.36 [95% CI 0.14-0.96], p = 0.041. There was no difference in SjD-PFS or overall survival between the two groups. Of note, none of the patients with anti-CD20 maintenance therapy relapsed (0% vs 36%, log-rank p = 0.04)Conclusion:In patients with SjD and MZ lymphoma, older age and pulmonary involvement were negatively associated with OS. Systemic first-line treatment of lymphoma reduced the risk of SjD relapse suggesting that in case of indecisiveness between treatment and watch and wait attitude, activity of SjD beyond lymphoma is a strong argument in favor of a systemic treatment. A combination of B-cell targeted therapy and chemotherapy may be considered for decreasing the risk of lymphoma relapse.Figure 1.A) Probability of Sjögren progression free survival according to systemic treatment vs no systemic treatment at lymphoma diagnosis, after propensity score adjustment. B) Probability of Lymphoma-PFS according to combotherapy vs monotherapy, after propensity score adjustment.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Maxime Beydon: None declared, Juliette Rocca: None declared, Véronique Le Guern: None declared, Eric Hachulla: None declared, Marion Couderc: None declared, Sandrine Jousse-Joulin: None declared, Valerie Devauchelle-Pensec: None declared, Jacques-Eric Gottenberg Abbvie, Astra Zeneca, Sanofi, Lilly, Galapagos, Gilead, Roche Chugai, Pfizer, Bristol Myer Squib, MSD, Pfizer, Abbvie, Lilly, Olivier Vittecoq: None declared, Christian Lavigne: None declared, Jean Schmidt: None declared, Claire Larroche: None declared, Xavier Mariette Astra Zeneca, Bristol Myer Squib, Galapagos, GSK, Novartis and Pfizer, Raphaèle Seror GSK, Bristol Myer Squib, Boerhinger and Janssen, Gaetane Nocturne: None declared.

Background:Sjögren’s disease (SjD) is a heterogenous autoimmune disease, with a wide range of symptoms, from dryness, fatigue, pain, to systemic manifestations, and an increased risk of lymphoma. Recently, three clusters of patients with SjD have been described based on unsupervised clustering analysis according to symptoms, clinical signs and biologic parameters: 1/ BA-LS (B-cell active with low symptoms); 2/ HSA (High systemic activity); 3/ LSA-HS (Low systemic activity with high symptoms). These findings suggest potential heterogeneity in pathophysiological mechanisms.Objectives:To investigate this hypothesis, we examined whether these three clusters were associated with distinct biomarkers.Methods:This study involved SjD patients meeting AECG criteria from the ASSESS cohort. The following biomarkers were measured in sera at the time of inclusion: for IFN pathways—IFN-alpha 2, IFN gamma, CXCL-10; for B cell activation—CXCL-13, BAFF, B2-microglobulin, FLT-3; for T cell activation—IL-7, CCL-19, TNF-RII. Additionally, the IFN signature was assessed using transcriptomic analysis. Kruskal-Wallis rank sum test was used to compare different clusters for continuous variables. Additionally, the risk of lymphoma and of new immunosuppressive drugs prescriptions were compared according to the IFN signature.Results:This analysis included 395 (94% female, median age 53 [43-63] years) patients from the ASSESS cohorts. The three clusters displayed differences in the IFN pathways (IFN signature), primarily driven by type I IFN (IFN-a2 level) elevated only in BA-LS and HSA clusters and not in the LSA-HS cluster (p=0.001). IFN gamma and CXCL-10 were not different between the 3 clusters.The same clusters that exhibit high level of type 1 IFN also had higher CXCL-13 levels (p=0.0032) reflecting B-cell activation, higher IL-7 (p=0.0042) and TNFRII (p<0.001) levels reflecting T-cell activation. Higher levels of FLT-3 were found in the HSA cluster. BAFF level was not different between the 3 clusters.Lastly, there were a trend indicating an increased risk of lymphoma in patients with positive IFN signature (HR 2.53; 95%CI 0.67–9.55), and an increased risk of immunosuppressant prescription during follow-up (HR 2.81; 95%CI 1.26-6.29).Conclusion:The two clusters BA-LS and HSA have a very distinct cytokine signature than the patients with LSA-HS. These two active clusters share a high type 1 IFN level, and elevated markers of both B-cell and T-cell activation. Patients from the BA-LS cluster being younger, it is likely that this cluster represent an earlier disease stage than HSA cluster. In order to go towards personalized medicine, work is in progress for deciphering patients in these two active clusters exhibiting one predominant pathways among type 1 IFN, B-cell and T-cell activation.REFERENCES:[1] Nguyen Y, Nocturne G, Henry J. Identification of distinct phenotypes of Sjögren disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts. Lancet Rheumatology 2024.Acknowledgements:The authors are indebted to all patients for their participation, and to all physicians who included patients in the Paris-Saclay and ASSESS cohorts. The Assessment of Systemic Signs and Evolution in Sjögren’s Syndrome (ASSESS) national multicenter prospective cohort was formed in 2006 with a French Ministry of Health grant (Programme Hospitalier de Recherche Clinique 2005 P060228). The ASSESS cohort is promoted by the French Society of Rheumatology and receives research grants from the French Society of Rheumatology.Disclosure of Interests:Yann Nguyen: None declared, Xavier Mariette Xavier Mariette received consulting fees from Astra Zeneca, Bristol Myer Squib, Galapagos, GSK, Novartis and Pfizer, Maxime Beydon: None declared, Divi Cornec: None declared, Jacques-Olivier Pers: None declared, Jacques MorelJacques Morel received honoraria from Abbvie, Boehringer Ingelheim, Biogen, Lilly, Mylan, Pfizer, Sanofi, Bristol Myers Squib, Fresenius Kabi, Galapagos, Medac, Novartis, Roche Chugai;,Jacques Morel received grants from Bristol Myers Squib, Fresenius Kabi, Lilly, Novartis, Pfizer, and Roche-Chugaï;, Aleth PERDRIGER: None declared, Emmanuelle Dernis Emmanuelle Dernis received consulting fees from BMS, Celgène, Lilly, MSD, Novartis, UCB; honoria for lectures from Abbvie, BMS, Janssen, Lilly, Medac, MSD, Novartis, Roche-Chugaï, Sanofi, UCB, Celgène, Amgen, Galapagos;, Valerie Devauchelle-Pensec: None declared, Damien Sene: None declared, Philippe Dieudé Philippe Dieudé received consulting fees from Pfizer, Roche Chugai, Bristol Myers Squibb, Abbvie, MSD., Philippe Dieudé received grants from Novartis, Marion Couderc: None declared, Anne-Laure Fauchais: None declared, Claire Larroche: None declared, Olivier Vittecoq: None declared, Carine Salliot Carine Salliot received Honoria from Novartis, Roche Chugaï, Eric Hachulla: None declared, Véronique Le Guern: None declared, Jacques-Eric Gottenberg Jacques-Eric Gottenberg consulting fees from Abbvie, Astra Zeneca, Sanofi, Lilly, Galapagos, Gilead, Roche Chugai, Pfizer, Bristol Myer Squib, MSD., Jacques-Eric Gottenberg received grants from Pfizer, Abbvie, Lilly, Raphaèle Seror Raphaèle Seror received consulting fees from GSK, Bristol Myer Squib, Boerhinger and Janssen; honoraria from GSK, Bristol Myer Squib, Boehringer, Amgen, Pfizer and Roche; travel fees from Amgen and GSK;, Gaetane Nocturne: None declared.

BackgroundPrimary Sjögren Syndrome (pSS) patients have an increased risk of Non-Hodgkin lymphoma (NHL). There is no consensus on the therapeutic management of low-grade NHL. Two strategies can be proposed; either a ‘‘wait and see’’ strategy or an active therapeutic strategy.ObjectivesTo describe characteristics of NHL in pSS, therapeutic strategies and impact of these strategies on prognosis of lymphoma and of pSS.MethodsThis multicentric retrospective study included all lymphoma patients of the ASSESS cohort, enriched with patients recruited in Rheumatology and Internal Medicine departments. For each patient, we collected biological and clinical manifestations of pSS, lymphoma’s characteristics, and treatment strategy. Progression free survival (PFS) (lymphoma-PFS and pSS relapse free survival) and overall survival (OS) were analyzed.ResultsA total of 106 pSS patients who presented a B cell lymphoma between 1985 and 2019 were included. Among them 14 (13%) had diffuse large B cell lymphoma (DLBCL) and 82 pSS patients presented a low-grade B cell-NHL, mucosa-associated lymphoid tissue (MALT) lymphomas being the most frequent histologic subtype occurring in 68/82 (83%) patients.Among these 82 patients, a “wait and watch strategy” was chosen in 19 (23%) patients; 63 patients received a specific treatment for lymphoma at lymphoma diagnosis including systemic treatment (chemotherapy and/or immunotherapy) in 49 (60%) patients and local therapy (surgery or radiotherapy) in 14 (17%) patients; 10 patients further received rituximab (RTX) maintenance therapy.Comparison of treated versus not treated patients is presented in the Table 1. Untreated patients were older and had less pulmonary lymphoma location.We then analyzed the prognosis after a mean follow up of 6.5 years. Nine patients (11%) died during the follow-up. In multivariate analysis, age (HR= 1.16 [1.06-1.27], p = 0.001) and pulmonary location (HR= 8.15 [1.57-42.3], p = 0.013) were associated with death.Last, we compared OS, lymphoma PFS and pSS relapse PFS in treated versus not treated patients after propensity score weighting We observed that starting an active treatment for NHL at lymphoma diagnosis did not impact OS and lymphoma PFS (HR= 4.81 [0.48-47.9], p=0.2 and HR=1.12 |0.50- 2.48], p=0.8, respectively). Conversely, treating lymphoma had a protective effect on the risk of pSS relapse (HR 0.4 [0.17-0.95], p = 0.038). Last, among patients treated for lymphoma, we observed that no lymphoma relapse occurred in patients who received maintenance therapy with RTX (0/10 events vs 18/53, p = 0.04).ConclusionThis study based on a large number of pSS patients with lymphoma shows that age and pulmonary location are independently associated with the risk of death. The choice of treating lymphoma at its diagnosis or not does not affect OS and PFS for lymphoma. However treatment of lymphoma reduced the risk of pSS relapse. This should be taken into account when deciding therapeutic strategy in our pSS patients with lymphoma.Table 1.VariableWait and watch N=19Active treatment N=63p-val.F18/ 19 (95%)54/ 63 (86%)Age64.0 (54.0, 75.5)56.0 (47.0, 65.5)0.041Time between pSS and lymphoma diagnosis1.0 (0.0, 8.5)3.2 (0.1, 9.0)0.6ESSDAI6.0 (4.0, 8.0)8.0 (5.0, 14.0)0.2clinESSDAI4.0 (3.0, 7.0)6.5 (4.0, 12.8)0.091BiologySSA antibodies14/ 19 (74%)44/ 61 (72%)0.9SSB antibodies8/ 19 (42%)23/ 58 (40%)0.9Positive rheumatoid factor14/ 18 (78%)39/ 54 (78%)0.8Low C42/ 11 (18%)15/ 35 (43%)0.2Hypergammaglobulinemia9/ 16 (56%)30/ 45 (67%)0.5Lymphoma type0.7MALT lymphoma15/ 19 (79%)53/ 63 (84%)Nodal marginal zone lymphoma4/ 19 (21%)10/ 63 (16%)Lymphoma disseminationSalivary and/or ganglionar limited7/ 19 (37%)35/ 63 (56%)0.2Lymphoma spread ≥ 2 locations9/ 19 (47%)28/ 63 (44%)0.8Lymphoma localizationSalivary gland limited lymphoma4/ 19 (21%)20/ 63 (56%)0.4Pulmonary lymphoma involvement0/ 19 (0%)13/ 63 (21%)0.032Salivary gland lymphoma involvement11/ 19 (58%)36/ 63 (57%)>0.9OutcomeMedian follow-up7.0 (4.5, 8.5)6.0 (4.0, 13.5)0.7Death1/ 19 (5.3%)8/ 63 (13%)-REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

To investigate and compare the pharmacokinetic (PK) profiles of MB02 products, before and after optimizing the manufacturing process, and reference bevacizumab to establish bioequivalence between them. In this randomized, double‐blind, single dose, parallel study, 114 healthy male volunteers were randomized 1:1:1 to receive a 1 mg/kg intravenous dose of MB02‐SP, MB02‐DM, or US‐bevacizumab. The follow‐up period was 100 days. PK similarity between them was determined using the standard bioequivalence criteria (0.80–1.25) for the area under the serum concentration–time curve from time 0 extrapolated to infinity and the maximum observed serum concentration. Study results showed that the PK profiles of bevacizumab were similar. Statistical analysis demonstrated that for each pairwise comparison there were no differences. The 90% CIs for the ratios of geometric least squares means were fully contained within the predefined similarity acceptance limits and ranged from 0.899 to 1.12 for area under the curve and from 0.887 to 1.11 for maximum concentration. A total of 159 adverse events were reported by 76 subjects who received the study drug. The majority (90.6%) of the reported adverse events were grade 1 in severity, with 9.4% as grade 2 in severity. None were considered as grade 3, 4, or 5. Treatment‐induced anti‐drug antibodies incidence was 21.6%, 33.3%, and 23.7% for the treatment of MB02‐SP, MB02‐DM, and US‐bevacizumab, respectively. No subjects showed treatment‐induced neutralizing anti‐drug antibodies. This study demonstrates the PK, safety, and immunogenicity similarity and bioequivalence of MB02‐SP, MB02‐DM, and the reference product bevacizumab. A randomized, double‐blind, single dose, parallel group study randomized 1:1:1 to receive a 1 mg/kg intravenous dose of MB02‐SP, MB02‐DM, or US‐bevacizumab in order to assess bioequivalence were conducted. One hundred and fourteenth healthy male subjects were randomized and followed for a period of 100 days. Pharmacokinetic similarity was determined using the standard bioequivalence criteria (0.80–1.25) for the area under the serum concentration–time curve from time 0 extrapolated to infinity and the maximum observed serum concentration.

External ventricular drainage (EVD) catheters provide reliable and accurate means of monitoring intracranial pressure and alleviating elevated pressures via drainage of cerebrospinal fluid (CSF). CSF infections occur in approximately 9% of patients. Antibiotic-impregnated (AI) EVD catheters were developed with the goal of reducing the occurrence of EVD catheter-related CSF infections and their associated complications. To present an international, prospective, randomized, open-label trial to evaluate infection incidence of AI vs standard EVD catheters. Infection was defined as (1) proven infection, positive CSF culture and positive Gram stain or (2) suspected infection: (A) positive CSF culture with no organisms identified on initial Gram stain; (B) negative CSF culture with a gram-positive or -negative stain; (C) CSF leukocytosis with a white blood cell/red blood cell count >0.02. Four hundred thirty-four patients underwent implantation of an EVD catheter. One hundred seventy-six patients in the AI-EVD cohort and 181 in the standard EVD catheter cohort were eligible for evaluation of infection. The 2 groups were similar in all clinical characteristics. Proven infection was documented in 9 (2.5%) patients (AI: 4 [2.3%] vs standard: 5 [2.8%], P = 1.0). Suspected infection was documented in 31 (17.6%) patients receiving AI and 37 (20.4%) patients receiving standard EVD catheters, P = .504. Duration of time to suspected infection was prolonged in the AI cohort (8.8 ± 6.1 days) compared with the standard EVD cohort (4.6 ± 4.2 days), P = .002. AI-EVD catheters were associated with an extremely low rate of catheter-related infections. AI catheters were not associated with risk reduction in EVD infection compared to standard catheters. Use of AI-EVD catheters is a safe option for a wide variety of patients requiring CSF drainage and monitoring, but the efficacy of AI-EVD catheters was not supported in this trial.

Although pulmonary function testing plays a key role in the diagnosis and management of chronic pulmonary conditions in children under 6 years of age, objective physiologic assessment is limited in the clinical care of infants and children less than 6 years old, due to the challenges of measuring lung function in this age range. Ongoing research in lung function testing in infants, toddlers, and preschoolers has resulted in techniques that show promise as safe, feasible, and potentially clinically useful tests. Official American Thoracic Society workshops were convened in 2009 and 2010 to review six lung function tests based on a comprehensive review of the literature (infant raised-volume rapid thoracic compression and plethysmography, preschool spirometry, specific airway resistance, forced oscillation, the interrupter technique, and multiple-breath washout). In these proceedings, the current state of the art for each of these tests is reviewed as it applies to the clinical management of infants and children under 6 years of age with cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheeze, using a standardized format that allows easy comparison between the measures. Although insufficient evidence exists to recommend incorporation of these tests into the routine diagnostic evaluation and clinical monitoring of infants and young children with cystic fibrosis, bronchopulmonary dysplasia, or recurrent wheeze, they may be valuable tools with which to address specific concerns, such as ongoing symptoms or monitoring response to treatment, and as outcome measures in clinical research studies.