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Clinical trials on carbon ion radiotherapy (C-ion RT) for the prostate cancer were conducted at the NIRS for over 20 years. The results so far have been quite satisfactory in both toxicity and tumour control. In addition, advancement of hypofractionation has been successfully progressed and 12-fraction C-ion RT could be established. To obtain the outcomes of multi-institutional clinical trials, a study group, J-CROS, was organized and conducts several multicenter clinical trials including the prospective study for the high-risk prostate cancer. It is expected that the outcomes of these clinical studies would result in widening the coverage of National Health Insurance for the C-ion RT. Technical progression has been also achieved at the NIRS. The scanning irradiation became available in 2011 and all the prostate cancers are treated with scanning at present. A new clinical trial of 4-fraction C-ion RT for the locally recurrent prostate cancer has been started using dose painting of scanning beam. The rotating gantry of heavy ion beam was also installed. These technical progressions enable to perform the intensity modulated ion therapy with carbon beam alone or with various ion species.

Background:Thrombotic microangiopathy (TMA) is associated with the progression of scleroderma renal crisis (SRC). TMA may be involved in normotensive renal crisis, which has a poor prognosis. A disintegrin-like and metalloprotease with thrombospondin type 1 repeats (ADAMTS)-13 is useful for the diagnosis of TMA, but its association in SRC has not been elucidated.Objectives:The aim of this study is to investigate the association of ADAMTS13 activities and inhibitors with SRC.Methods:SRC events were extracted from the Kyoto University Systemic Sclerosis Registry (n = 330). ADAMTS13 activity and its inhibitors in sera at the onset of SRC were measured. The associations between ADAMTS13 and clinical information including hemolytic anemia, renal function, and 1-year survival were analyzed. ADAMTS13 activity was compared in the two groups classified by 1-year survival or induction of hemodialysis by using Mann-Whitney U test and Fisher’s exact test. Hypertension was defined as systolic blood pressure ≥130 mmHg, and malignant hypertension as diastolic blood pressure ≥110 mmHg.Results:SRC events were observed in 24 of the 330 patients with systemic sclerosis (SSc). Hemolytic anemia (n = 21, 88%), thrombocytopenia (n = 18, 75%), fever (n = 19, 76%) and psychiatric symptoms (n = 2, 8%) were observed. All patients with SRC were treated with ACE inhibitors, resulting in high frequencies of induction of hemodialysis (n = 15, 63%) and inadequate 1-year survival (n = 13, 54%).The 1-year survival rates were observed for patients with hypertension (n = 12/20, 60%) and normotension (n = 1/4, 25%) (p = 0.30). Furthermore, the 1-year survival rates were for patients with malignant hypertension (n = 9/13, 69%) and non-malignant hypertension (n = 4/11, 36%) (p = 0.22).ADAMTS13 at the onset was measured in 15 patients. None were positive for ADAMTS13 inhibitors. ADAMTS13 activity was 44.0 ± 17.8(%) (normal range, 50-150%) (Figure 1). ADAMTS13 activity was mildly decreased in all patients, and was under normal levels in 8 patients. There were no subjects under 10% in ADAMTS13 activity, the baseline level referred to thrombotic thrombocytopenic purpura (TTP). ADAMTS13 activity was not significantly correlated with levels of hemoglobin and platelet.When ADAMTS13 activity was compared in the two groups classified by 1-year survival or induction of hemodialysis, there were no significant differences between the two groups: survived patients, 36.9 ± 14.0% vs. deceased patients, 50.3 ± 17.3% (p = 0.15); patients without hemodialysis, 46.1 ± 16.3% vs. patients with hemodialysis, 43.5 ± 17.4% (p = 0.83).Conclusion:Normotensive renal crisis tended to have a poor prognosis. ADAMTS13 activity was slightly decreased at the onset of SRC. ADAMTS13 inhibitors were not detected. There was no significant association between ADAMTS13 activity with outcomes of SRC.REFERENCES:[1] Autoantibody profiles associated with morbidity and mortality in scleroderma renal crisis.[2] Tsuji H, Kuramoto N, Sasai T, Shirakashi M, Onizawa H, Kitagori K, Akizuki S, Nakashima R, Watanabe R, Onishi A, Murakami K, Yoshifuji H, Tanaka M, Hashimoto M, Ohmura K, Morinobu A. Rheumatology (Oxford). 2022 Oct 6;61(10):4130-4135. doi: 10.1093/rheumatology/keac047.Figure 1.ADAMTS13 activity at the onset of SRC.N=15. The dotted lines show normal range (50-150%) and the baseline level referred to thrombotic thrombocytopenic purpura (under 10%).Acknowledgements:NIL.Disclosure of Interests:None declared.

BackgroundSpecific haplotypes of human leukocyte antigen (HLA) are associated with susceptibility and disease activity of Behçet’s disease (BD). However, the clinical importance of HLA-A26 in BD is not well recognized compared to that of HLA-B51.ObjectivesThis study aimed to examine the association between HLA-A26, HLA-B51, clinical manifestations, and disease severity in BD, especially focusing on HLA-A26 possession.MethodsThis study was a multicenter cross-sectional observational study and patients with BD were enrolled from 2006 to 2021. All patients met the International Criteria for BD [1] or the diagnostic criteria of the Behçet’s Disease Research Committee of Japan [2]. Disease severity was evaluated using Krause score reflecting the entire spectrum of disease manifestations [3]. Both serotypes and genotypes were accepted for HLA typing.ResultsIn total, 200 patients were enrolled in this study. Uveitis was observed in 95/196 patients (48.5%) and gastrointestinal involvement in 57/167 patients (34.1%). HLA haplotypes were identified for HLA-B51 (n = 52/106, 49.1%), HLA-A26 (n = 25/88, 28.4%), and both HLA-B51 and HLA-A26 (n = 6/88, 6.8%). While HLA-A26 showed no significant association with clinical manifestations without adjustment for HLA-B51, HLA-A26 possession showed a higher frequency of uveitis (HLA-A26 positive vs. negative: n = 6/6, 100% vs. n = 16/32, 50.0%, respectively, p = 0.03) and higher Krause scores (median: 7 vs. 5, respectively, p = 0.02) under conditions with HLA-B51. Furthermore, the association between uveitis and gastrointestinal involvement was influenced by HLA-A26: HLA-A26 possession was associated with a higher frequency of uveitis in patients with gastrointestinal involvement (HLA-A26 positive vs. negative: n = 5/9, 55.6% vs. n = 0/21, 0%, respectively, p = 0.001), as well as for gastrointestinal involvement in patients with uveitis (HLA-A26 positive vs. negative: n = 5/11, 45.5% vs. n = 0/24, 0%, respectively, p = 0.001). All 5 patients with both uveitis and gastrointestinal involvement had HLA-A26 (HLA-A26 positive vs. negative: n = 5/21, 23.8% vs. n = 0/58, 0%, respectively, p = 0.001).ConclusionHLA-A26 was associated with severity of BD and uveitis in patients with HLA-B51, and was associated with coexistence of uveitis and gastrointestinal involvement. This study suggested the importance of confirming HLA-A haplotype in patients with BD.References[1]J Eur Acad Dermatol Venereol. 2014; 28(3): 338-47.[2]Y Mizushima, G Inaba, Y Mimura. Report of Behçet’s Disease Research Committee, Japan; 1987. 8-17.[3]I Krause, et al. J Rheumatol. 2001; 28(5): 1033-6.Table 1.Comparison of clinical characteristics of BD patients with and without HLA-A26Total(n = 88)HLA-B51 (+)(n = 38)Uveitis (+)(n = 40)Gastrointestinalinvolvement (+)(n = 30)Uveitis†, %56.0 vs. 41.3, p = 0.24100 vs. 50.0, p = 0.03-55.6 vs. 0, p = 0.001Gastrointestinal involvement†, %42.9 vs. 36.2, p = 0.6160.0 vs. 24.1, p = 0.1445.5 vs. 0, p = 0.001-Uveitis + Gastrointestinal involvement†, %23.8 vs. 0, p = 0.00160.0 vs. 0, p = 0.002--Krause score¶, mean6 vs. 5, p = 0.437 vs. 5, p = 0.027 vs. 6, p = 0.276.5 vs. 5, p = 0.04†: HLA-A26 positive (%) vs. negative (%); Fisher’s exact test ¶: HLA-A26 positive vs. negative; Mann-Whitney U testFigure 1.Association between haplotypes and clinical manifestationsAcknowledgements:NIL.Disclosure of InterestsNone Declared.

Background: The purpose of this study was to evaluate the feasibility of a new shortened 3-week treatment schedule of carbon ion radiotherapy (CIRT) for prostate cancer. Methods: Beginning in May 2010, patients with T1b–T3bN0M0, histologically proven prostate adenocarcinoma were enrolled in the phase II trial of CIRT. Patients received 51.6 GyE in 12 fractions over 3 weeks (protocol 1002). The primary end point was defined as the incidence of late adverse events that were evaluated based on the Common Terminology Criteria for Adverse Events version 4.0. Biochemical failure was determined using the Phoenix definition (nadir +2.0 ng ml −1 ). Results: Forty-six patients were enrolled, and all patients were included in the analysis. The number of low-, intermediate-, and high-risk patients was 12 (26%), 9 (20%), and 25 (54%), respectively. The median follow-up period of surviving patients was 32.3 months. Two patients had intercurrent death without recurrence, and the remaining 44 patients were alive at the time of this analysis. In the analysis of late toxicities, grade 1 (G1) rectal haemorrhage was observed in 3 (7%) patients. The incidence of G1 haematuria was observed in 6 (13%) patients, and G1 urinary frequency was observed in 17 (37%) patients. No ⩾G2 late toxicities were observed. In the analysis of acute toxicities, 2 (4%) patients showed G2 urinary frequency, and no other G2 acute toxicities were observed. Conclusions: The new shortened CIRT schedule over 3 weeks was considered as feasible. The analysis of long-term outcome is warranted.

Background:Systemic lupus erythematosus (SLE) is more likely to occur in young women, and it has been reported that it affects the health of mothers and children during pregnancy and childbirth. SLE patients have fewer children than healthy subjects, and contributing factors are thought to include older age, thyroid dysfunction or antiphospholipid syndrome (APS) comorbidities, history of cyclophosphamide (CYC) use, non-steroidal anti-inflammatory drugs (NSAID) or high-dose glucocorticoid use, and elevated SLE Disease Activity Index (SLEDAI) scores 1). However, there are few reports on the effects of aging, social factors, and psychological factors on pregnancy by direct survey for patients.Objectives:We analyzed the influence of disease-related factors, social factors, and psychological factors on the number of children for SLE patients.Methods:We conducted a questionnaire about thoughts and desires regarding pregnancy and relationships with surrounding people and collected medical record information from SLE patients in Kyoto Lupus Cohort registry. Patients were classified into 2 groups by their age of onset: SLE onset before the age of 40 (early onset group) and SLE onset after 40 years old (late onset group). For comparison between two groups, Student t-test and Mann-Whitney U test were performed. A multiple regression analysis was performed to examine the effects of APS comorbidity, nephropathy, history of CYC use, intentional avoidance of pregnancy, and age at first birth at age 30 or older on the number of children. Data were analyzed with R (ver 4.0.2). P values less than 0.05 were considered significant.Results:Of the 277 SLE patients who responded to the questionnaire (response rate 87%), 262 were women, and 207 (79.0%) were in the early onset group and 53 patients (20.2%) were in the late onset group.There was a significant difference in the mean number of children between the early onset group (0.75) and the late onset group (1.48) (p <0.01). There were no significant differences in APS comorbidities, nephropathy, history of CYC use, intentional avoidance of pregnancy, and mean age at first birth between the two groups. A significant correlation was observed between the age of onset with the number of children in the early onset group (ρ = 0.30, p < 0.01, Figure 1(A)), while no significant correlation was observed between them in the late onset group (ρ = 0.06, p = 0.67).Intentional avoidance of pregnancy (β = -0.35, p = 0.036) and age at first birth older than 30 years (β = -0.67, p < 0.01) showed significant associations with number of children by multivariate analysis in the early-onset group.In the questionnaire, many patients consulted their doctor or partner about pregnancy, but some were unable to consult with others and avoided pregnancy. In addition, it was found that many patients avoided pregnancy because of the possibility that the drugs they were taking might affect their children or because their SLE was highly active. (Table 1)Furthermore, there was a significant negative correlation between age at first birth and number of children (ρ = -0.48, p < 0.01, Figure 1(B)).Conclusion:This analysis revealed disease-related, social factors, and psychological factors that influence pregnancy. Since the environment for pregnancy of SLE patients were underdeveloped, it was suggested that conception planning in SLE patients could be improved by the support through appropriate consultation and patient guidance, and appropriate treatments using medication not affecting pregnancy.REFERENCES:[1] Stamm B, Barbhaiya M, Siegel C, Lieber S, Lockshin M, Sammaritano L. Infertility in systemic lupus erythematosus: what rheumatologists need to know in a new age of assisted reproductive technology. Lupus Sci Med. 2022 Dec;9(1):e000840.Acknowledgements:NIL.Disclosure of Interests:None declared.

Aims/hypothesis The aims of this study were to assess the clinical significance of introducing HbA 1c into a risk score for diabetes and to develop a scoring system to predict the 5 year incidence of diabetes in Japanese individuals. Methods The study included 7,654 non-diabetic individuals aged 40–75 years. Incident diabetes was defined as fasting plasma glucose (FPG) ≥7.0 mmol/l, HbA 1c ≥6.5% (48 mmol/mol) or self-reported clinician-diagnosed diabetes. We constructed a risk score using non-laboratory assessments (NLA) and evaluated improvements in risk prediction by adding elevated FPG, elevated HbA 1c or both to NLA. Results The discriminative ability of the NLA score (age, sex, family history of diabetes, current smoking and BMI) was 0.708. The difference in discrimination between the NLA + FPG and NLA + HbA 1c scores was non-significant (0.836 vs 0.837; p  = 0.898). A risk score including family history of diabetes, smoking, obesity and both FPG and HbA 1c had the highest discrimination (0.887, 95% CI 0.871, 0.903). At an optimal cut-off point, sensitivity and specificity were high at 83.7% and 79.0%, respectively. After initial screening using NLA scores, subsequent information on either FPG or HbA 1c resulted in a net reclassification improvement of 42.7% or 52.3%, respectively ( p  < 0.0001). When both were available, net reclassification improvement and integrated discrimination improvement were further improved at 56.7% (95% CI 47.3%, 66.1%) and 10.9% (9.7%, 12.1%), respectively. Conclusions/interpretation Information on HbA 1c or FPG levels after initial screening by NLA can precisely refine diabetes risk reclassification.

BackgroundEpoxy fatty acids (EpFA), cytochrome P450(CYP)-mediated metabolites of polyunsaturated fatty acids (PUFA), have anti-inflammatory effects[1]. However, EpFA is quickly converted to an inactive form by the soluble epoxide hydrolase(sEH). In recent years, the efficacy of sEH inhibitors (sEHi) has been reported in a variety of diseases[2-4]. However, compared to ω-6 epoxides, such as epoxyeicosatirienioic acids (EET) derived from arachidonic acid (AA), there are few reports on ω-3 epoxides, epoxyeicosapentaenoic acid (EEQ) from eicosapentaenoic acid (EPA) and epoxydocosapentaenoic acids (EDP) from docosapentaenoic acid (DHA)5), and their effects on arthritis are not well understood.ObjectivesTo investigate and compare the effects of ω-6 and ω-3 epoxides on inflammatory arthritis.MethodsCollagen induced arthritis (CIA) were treated with three different diets (ω-6 PUFA rich, ω-3 PUFA rich, and Control) and two types of drinking solution, one containing sEHi and the other containing only polyethylene glycol as solvent control (total 6 groups, 8 mice each). Arthritis and pathological scores were evaluated, and feces were collected before the onset of arthritis (day 25) for intergroup comparative analysis of bacterial flora.ResultsIn all the dietary groups, there was a tendency for arthritis scores to decrease with sEHi administration, but the incidence of arthritis, arthritis scores, and pathological scores decreased dramatically in the group fed with the ω-3 rich diet and sEHi combination. The groups fed the ω-6 rich diet and Control diet showed almost similar results. In the ω-3 rich diet and sEHi combination group, showed an increase in a certain specific bacterial strain.Conclusionω-3 epoxides were found to be more effective in reducing arthritis, and changes in intestinal bacteria may have influenced this pathological change.References[1]Shi, Z. et al. CYP450 Epoxygenase Metabolites, Epoxyeicosatrienoic Acids, as Novel Anti-Inflammatory Mediators. Molecules 2022,27,3873[2]Sandra, C. et al. Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease. J.Med.Chem,2022,65,4909-4925[3]Merce, P.et al. Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy.Biomolecules 2020, 10, 703; doi:10.3390/biom10050703[4]Rebecca, L.et al. Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase. PNAS,2014,22,111,8167-8172[5]Yang, Y. et al. Differential Effects of 17,18-EEQ and 19,20-EDP Combined with Soluble Epoxide Hydrolase Inhibitor t-TUCB on Diet-Induced Obesity in Mice. Int. J. Mol. Sci. 2021,22,8267g. Characters from table content including title and footnotes.Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

BackgroundThe QRISK3, an atherosclerotic cardiovascular disease (ASCVD) risk tool including SLE as a risk factor, has been reported to demonstrate better performance in predicting risk of ASCVD in SLE patients compared with Framingham risk score (FRS) [1]. However, it is unknown how the QRISK3, the risk score established in the United Kingdom (UK), can estimate the ASCVD risk of Japanese SLE patients in comparison to the risk score validated for the Japanese population.ObjectivesTo compare two algorithms for ASCVD risk estimation, QRISK3 and Hisayama study score [2], a general risk calculator used in Japan Atherosclerosis Society (JAS) guideline for Prevention of Atherosclerotic Cardiovascular Diseases 2022, in our cohort of Japanese SLE patients.MethodsWe performed a cross-sectional study in SLE patients attending Kyoto University Hospital by using questionnaires and laboratory tests. In primary prevention subjects without high-risk comorbidities (peripheral artery disease, chronic kidney disease, diabetes) and aged 40 to 79, both the Hisayama study score based on traditional risks (sex, systolic blood pressure, glucose intolerance, serum lipid and smoking) and QRISK3 (ethnicity was selected as “Other Asians”) were calculated to estimate the ASCVD risk over the next 10 years.ResultsAmong 335 patients enrolled, 105 were eligible for both ASCVD risk calculators. QRISK3 estimated 46 patients as high risk (score >10 %), while the Hisayama study score classified no patients as high risk. The patients classified as high risk by QRISK3 had significantly higher Hisayama study score (4.71 [3.99-5.43] vs 2.28 [1.77-2.80], p<0.0001) and more traditional risks, such as old age (59.8 [57.6-62.1] vs 48.1 [46.8-49.4], p<0.0001), current smoking (9 [19.5%] vs 3 [5%], p=0.02) and hypertension on treatment (22 [47.8%] vs 7 [11.8%], p<0.0001) than the patients with low-moderate risk (Table1). QRISK3 score was positively correlated with the Hisayama study score (r=0.4945, p<0.0001). As a reference for each risk stratification score, the proportions to achieve target values for serum low-density lipoprotein cholesterol (LDL-C) recommended by the JAS guideline were 94.3 % and 69.5 % respectively.Figure 1.Table 1.Comparison between patients classified as high risk and low to moderate risk by QRISK3Low-moderate risk (n=59)High risk (n=46)P-valueThe Hisayama study score2.28 (1.77-2.80)4.71 (3.99-5.43)＜0.0001*Female (%)58 (98.3)42 (91.3)0.16Age, years48.1 (46.8-49.4)59.8 (57.6-62.1)＜0.0001*Disease duration, years19.0 (16.6-21.5)20.2 (16.8-23.6)0.56SLEDAI-2K5.18 (4.02-6.35)5.76 (3.92-7.59)0.59Prednisolone (PSL) (%)51 (86.4)40 (86.9)0.93Daily intake of PSL (mg)4.79 (3.77-5.82)4.8 (2.97-6.62)0.99Body mass index, kg/m220.9 (20.16-21.74)21.4 (20.4-22.4)0.43Current smokers (%)3 (5.0)9 (19.5)0.02**Family history of early CVD (%)4 (6.7)6 (13.0)0.32Systolic blood pressure (mmHg)119 (115-123)135 (130-139)＜0.0001*Antihypertensive therapy (%)7 (11.8)22 (47.8)＜0.0001***Glucose intolerance (%)26 (44.0)29 (63.0)0.05Serum LDL-C (mg/dL)111 (105-117)115 (104-126)0.52Serum HDL-C (mg/dL)75 (69-80)70 (63-76)0.21* student t-test ** Fisher exact test *** Pearson’s chi-square testConclusionQRISK3 classified more Japanese SLE patients as high risk of ASCVD when compared to the Hisayama study score. Lipid management might be insufficient according to QRISK3. The validation of QRISK3 by longitudinal studies should be warranted in Japanese SLE patients.References[1]Lisa Zhu et al. Assessing the validity of QRISK3 in predicting cardiovascular events in systemic lupus erythematosus. Lupus Sci Med. 2022 Feb;9(1):e000564.[2]Takanori Honda et al. Development and Validation of a Risk Prediction Model for Atherosclerotic Cardiovascular Disease in Japanese Adults: The Hisayama Study. J Atheroscler Thromb. 2022 Mar 1;29(3):345-361.Acknowledgements:NIL.Disclosure of InterestsTomohiro Kozuki: None declared, Hideaki Tsuji: None declared, Yudai Takase: None declared, Yuto Nakakubo: None declared, Takeshi Iwasaki: None declared, Tsuneyasu Yoshida: None declared, Mirei Shirakashi: None declared, Hideo Onizawa: None declared, Ryosuke Hiwa: None declared, Koji Kitagori: None declared, Syuji Akizuki: None declared, Ran Nakashima: None declared, Akira Onishi: None declared, Masao Tanaka: None declared, Hajime Yoshifuji Grant/research support from: GlaxoSmithKline (GSK), Akio Morinobu: None declared.

Background:C-reactive protein (CRP), one of the inflammatory markers, has been previously reported to be relatively low in systemic lupus erythematosus (SLE) patients, except in the presence of specific organ involvement such as serositis [1]. By contrast, CRP is a predictor of atherosclerotic diseases [2], which may be caused by SLE itself or medications for SLE and are frequently complicated with SLE as organ damage. However, it is unclear whether CRP predicts Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) progression in inactive SLE.Objectives:This study aimed to examine the association between CRP levels and organ damage in SLE patients with low disease activity.Methods:This multi-center, retrospective observational study used Lupus Registry of Nationwide Institutions (LUNA) cohort database. SLE patients who met Lupus Low Disease Activity State (LLDAS) at registration were divided into two groups: those with serum CRP levels ≥ 0.07 mg/dL (high CRP group) or < 0.07 mg/dL (low CRP group) both at registration and in the first year. The cutoff for CRP levels was determined as the median value in patients who met LLDAS. SDI progression was defined when the score increased ≥1.Results:Among 106 SLE patients who met LLDAS, 55 were in a high CRP group and 51 were in a low CRP group. In the high CRP group, patients were older (median: 56.8 vs. 41.6, p = 0.002), had higher body mass index (median: 22.6 vs. 20.3, p < 0.001), and had higher SDI scores (median: 1 vs. 0, p = 0.03) at registration. Log-rank test showed that the probability of SDI progression within 2 years was significantly higher in the high CRP group (p = 0.007) (Figure 1). Furthermore, Cox proportional hazard model showed that high CRP group was significantly associated with SDI progression when adjusted for age, SLE disease activity index scores, and SDI scores at baseline (HR: 2.72, 95% CI: 1.06-6.99, p = 0.04) (Table 1).Conclusion:CRP levels were associated with SDI progression within 2 years in LLDAS patients. Even in patients with inactive SLE, positive CRP levels may suggest the necessity to modify treatment for SLE or atherosclerotic risk factors.REFERENCES:[1] M Aringer. J Autoimmun. 2020: 110: 102374.[2] J Danesh, et al. N Engl J Med. 2004; 350(14): 1387-97.Figure 1.Table 1.UnivariateClinically importantVariablesHR (95% CI)p valueHR (95% CI)p valueClinical characteristicsAge, years1.02 (1.00 to 1.05)0.081.02 (0.99 to 1.05)0.16Female, %0.95 (0.33 to 2.78)0.93Disease duration, years1.02 (0.98 to 1.05)0.45BMI, kg/m21.00 (0.91 to 1.10)>0.99SLEDAI score1.05 (0.81 to 1.36)0.711.13 (0.86 to 1.48)0.39SDI score0.96 (0.64 to 1.43)0.830.74 (0.47 to 1.17)0.20High CRP, %2.81 (1.17 to 6.76)0.022.72 (1.06 to 6.99)0.04MedicationsCurrent PSL dose, mg/day1.00 (0.84 to 1.20)0.96HCQ, %0.49 (0.15 to 1.68)0.26Immunosuppressants, %0.73 (0.33 to 1.60)0.43BMI, body mass index; CRP, C-reactive protein; HCQ, hydroxychloroquine; HR, hazard ratio; PSL, prednisolone; SDI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; SLEDAI, systemic lupus erythematosus disease activity indexAcknowledgements:NIL.Disclosure of Interests:None declared.

Growing evidence reveals a pathological role of somatic mutations in various autoimmune diseases, such as the mutation in UBA1 in VEXAS syndrome, CARD11 and KLHL6 in cryoglobulinemic vasculitis, or STAT3 in Felty's syndrome[1]. Somatic mutations might also be involved in the pathogenesis of ANCA-associated vasculitis (AAV), which typically manifests in middle-aged and elderly individuals. We aimed to identify somatic mutations in patients with AAV. We collected whole blood and obtained peripheral blood mononuclear cells (PBMCs) and neutrophils from patients with AAV in active-disease status (n=16), as well as from patients with other autoimmune diseases (n=8) as disease controls, and healthy subjects (n=10). In addition, we collected these specimens from 12 out of the 16 patients with AAV after remission induction. We performed RNA sequencing (RNA-seq) on the obtained cells and whole genome sequencing (WGS) on DNA extracted from the whole blood. Somatic mutations were detected by comparing the RNA and DNA sequences[2]. After stringent quality control, we identified 108 somatic mutations across 16 patients in active-disease status. The mean coverage of RNA-Seq at the mutation site was 100.9 ± 367.8 ×, and that of WGS was 14.4 ± 4.3 ×, while the mean allele fraction was 22.9 ± 20.5%. One or more mutations were detected in each of the 15 (93.8%) patients. The median mutation count of each patient was 4.0, which was not significantly different from disease controls or samples after remission induction. We mapped one gene to each of the 108 mutations, resulting in 95 genes in total. Mutations for six of the 95 genes were observed in two or more patients, and two of them were related to the ubiquitin system. Of the 108 mutations, 37 were missense, and 20 were predicted to be deleterious (combined annotation-dependent depletion Phred score > 20). Among the 20 mutations, the HIST2H2AC mutation (NM_003517: p.L86P) in neutrophils was observed in two patients. To evaluate the functional outcome of the 20 mutations, we analysed the data on knocking out the corresponding genes using CRISPR in K562 cells[3]. The results showed that the expression of genes related to antigen presentation was increased in HEATR1 and RPL18 knockouts. When we followed up with 12 of the 16 patients after remission induction, 81.4% of the somatic mutations were no longer detected. Additionally, 91.7% of the deleterious mutations disappeared. We found somatic mutations with potential pathological effects in some patients with AAV exhibiting active-disease status. Notably, the majority of these mutations were not detected after remission induction. [1]Mustjoki, S. & Young, N. S. Somatic Mutations in ‘Benign’ Disease. N. Engl. J. Med. 384, 2039–2052 (2021). [2]Yizhak, K. et al. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 364, (2019). [3]Replogle, J. M. et al. Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq. Cell 185, 2559-2575.e28 (2022). The present study was supported in part by JSPS KAKENHI. (Grant No. 19H03209). None Declared.