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Background:Acute exacerbation (AE) is a life-threatening complication in connective tissue disease (CTD) associated interstitial lung disease (ILD) (CTD-ILD), including rheumatoid arthritis (RA). Although several risk factors for AE in CTD-ILD have been suggested, these are inconsistent. Krebs von den Lungen-6 (KL-6) is reported as a useful blood marker to detect severe CTD-ILD and RA-ILD, and serum KL-6 levels are significantly higher in patients with AE than in those without AE in RA-ILD patients [1]. However, the predictive value of KL-6 for AE in CTD-ILD or RA-ILD has not been completely confirmed.Objectives:To investigate the predictive factors for AE including initial serum KL-6 levels at RA-ILD onset and sequential changes of KL-6. We also examined the causal relationship between AE and mortality of RA-ILD patients.Methods:We retrospectively reviewed 115 patients with RA-ILD treated in our hospital between 2005 and 2019. Suspected drug-induced pneumonia cases or patients with other coexisting CTD were excluded. Cox regression analyses was used for univariate analysis to detect predictors of AE. Overall survival rate, respiratory-related deaths-free survival rate and AE-free survival rate were analyzed using the Kaplan-Meier method. P < 0.05 was considered statistically significant.Results:Among 115 patients, 29 patients (25.2%) developed AE and 32 patients (27.8%) died. The median follow-up period (IQR) was 57 (25.0-91.5) months, 57.4% were female and the mean age at RA-ILD onset was 72.2 ± 7.9 years old throughout the whole cohort. Among the AE group, methotrexate (MTX), tumor necrosis factor α inhibitor (TNFi) and non TNFi biological-DMARDs were used at AE onset in 10.7%, 0.0%, and 3.6% of patients, respectively. There was a significant difference of serum KL-6 levels at AE onset between AE group and non-AE group (1081.9 ± 624.7 vs 556.1 ± 285.6 U/mL, p < 0.001). Initial serum KL-6 levels at RA-ILD onset in AE group were higher than those in non-AE group, without a significant difference (648.9 ± 325.7 vs 523.7 ± 276.8 U/mL, p = 0.050). The optimal cut-off level of initial serum KL-6 to predict AE was 551 U/mL according to ROC analysis. In univariate analysis, the following factors were significantly associated with AE; usual interstitial pneumonia (UIP) pattern on HRCT at AE onset (Hazard Ratio [HR]: 2.18; 95% confidence interval [CI]: 1.02-4.61; p = 0.045), initial serum KL-6 > 551 U/mL at RA-ILD onset (HR: 2.46; 95%CI: 1.17-5.43; p = 0.018), increasing serum KL-6 levels > 10% before AE onset compared to the previous year (ΔKL-6 > 10%/year) (HR: 4.98; 95%CI: 2.17-11.84; p < 0.001). Initial serum KL-6 > 551 U/mL at RA-ILD onset and ΔKL-6 > 10%/year before AE were also significant prognostic factors for AE when we analyzed only in non-UIP patients (HR: 2.84; 95%CI: 1.15-7.35; p = 0.024, HR: 9.49; 95%CI: 3.02-36.25; p < 0.001, respectively). Conversely, median age at RA-ILD diagnosis, positive ratio of anti-CCP antibody, smoking habits, respiratory comorbidities, SDAI score, and therapeutics at both RA-ILD and AE onset had no significant associations with AE. Patients with initial serum KL-6 > 551 U/mL at RA-ILD onset and ΔKL-6 > 10%/year before AE had a significantly worse AE-free survival rate compared to others (p < 0.001). (Figure 1). Moreover, patients with AE had significantly lower overall survival rate (p < 0.001) and respiratory-related deaths-free survival rate (p < 0.001) than those without AE.Figure 1.KL-6 was measured at RA-ILD onset. ΔKL-6 means the annual variation ratio of KL-6 before AE. The survival curve using the Kaplan Meier method (Log rank test).Conclusion:Serum KL-6 levels at the disease onset and its sequential changes may be able to predict AE in the near future and support the early detection of AE in RA-ILD patients.References:[1]Sarcoidosis Vasc Diffuse Lung Dis. 2016 Oct 7; 33 (3):216-223.Disclosure of Interests:Nozomi Tanaka: None declared, Keisuke Nishimura Speakers bureau: Mitsubishi Tanabe Pharma Corporation. Pfizer Inc. Kyowa Kirin Co., Ltd. Chugai Pharmaceutical Co., Ltd. ONO PHARMACEUTICAL CO., LTD. Japan Blood Products Organization. Kissei Pharmaceutical Co., Ltd. Astellas Pharma Inc. AYUMI Pharmaceutical Corporation. Eisai Co., Ltd. DAIICHI SANKYO COMPANY. Norvartis AG. Bayer AG. Sanofi K.K., Daisuke Waki Speakers bureau: Mitsubishi Tanabe Pharma, AbbVie Inc, eisai Co,. Ltd, ONO PHARMACEUTICAL CO., LTD, Keiichiro Kadoba: None declared, Tomohiro Yoshida: None declared, Hiroyuki Murabe: None declared, Toshihiko Yokota: None declared

Background:Skeletal muscle is known as one of the organ involvements of primary systemic vasculitis.1,2 Muscle inflammation is detected by magnetic resonance imaging, and necrotizing vasculitis is proved by muscle biopsy.3 As with systemic vasculitis or single organ vasculitis, glucocorticoid (GC) and immunosuppressants are used in its treatment.4 There are not many reports about muscular vasculitis, and its long-term clinical course after initial treatment, including the rates of relapse and mortality, remains unclear.Objectives:To identify the predictors of relapse and mortality in patients with muscular vasculitis, especially focusing on the status of anti-neutrophil cytoplasmic antibody (ANCA).Methods:We retrospectively reviewed patients diagnosed with necrotizing vasculitis with muscle involvements in our hospital between 2004 and 2020. In all cases, muscular vasculitis was identified by muscle biopsy or magnetic resonance imaging. To focus on the clinical features of muscular vasculitis, we excluded patients with such severe organ involvements as cardiovascular, abdominal, cerebral, severe renal, and severe pulmonary involvements. We compared the 5-year cumulative incidence of relapse, the overall survival rate, and the dose of GC over 5 years between the ANCA-positive and ANCA-negative groups. A relapse was defined as any new or worsened state of disease activity requiring an escalation of GC dose. Gray’s method was used for assessing the cumulative incidence of relapse. The log-rank test was used for assessing overall survival. The Mann-Whitney U test was used for assessing the dose of GC. The possible factors for relapse in 5 years in a univariate analysis were selected for a multivariate analysis using the Cox proportional hazards model.Results:Forty-nine patients were enrolled. The median age of onset was 77 (69-82) years and 71.4% were women. There were 30 ANCA-positive patients (90.0% with anti-myeloperoxidase) and 19 ANCA-negative patients. The median age and the number of patients with renal involvements were higher in the ANCA-positive group than in the ANCA-negative group (73.0 ± 9.29 years vs. 79.5 ± 20.28 years, p=0.0062 and 7/30 [23.3%] vs. 0/19 [0.0%], p=0.034, respectively). The Birmingham Vasculitis Activity Score (ver. 3), the induction dose of GC, and the rate of immunosuppressants use were not significantly different between the two groups. During the observational period, 24 patients relapsed. The 5-year cumulative incidence of relapse was significantly higher in the ANCA-positive group than in the ANCA-negative group (p=0.026) (Figure 1). The Cox proportional hazards model revealed that the presence of ANCA was an independent risk factor for relapse (hazard ratio: 3.15; 95% confidence interval 1.06–9.38; p=0.040). During the observational period, 9 patients died (3 died from cancer, 1 from interstitial pneumonia, 1 from cerebral hemorrhage, 1 from infection, and 3 from unknown reasons). The ANCA-positive group exhibited a higher mortality rate than the ANCA-negative group without a statistical significance (p=0.12). The 5-year cumulative dose of GC was larger in the ANCA-positive group than in the ANCA-negative group without a statistical significance (14786 [11246–19138] mg vs. 10088 [7129–12634] mg, p=0.12).Conclusion:In muscular vasculitis, the presence of ANCA is an independent risk factor for long-term relapse. Stratified treatment depending on the ANCA status may reduce the relapse rate and the occurrence of side effects of GC in patients with muscular vasculitis.References:[1]Kitching AR et al. Nat Rev Dis Primers 2020; 6(1): 71.[2]Hernández-Rodríguez J et al. J Autoimmun 2014; 48-49: 84-9.[3]Ushiyama S et al. Rheumatol Int 2020; 40(10): 1667-74.[4]Ganeshanandan LR et al. Semin Arthritis Rheum 2020; 50(3): 503-8.Disclosure of Interests:None declared

Background:There are several reports that cytomegalovirus (CMV) reactivation resulted in more co-infections affecting survival in rheumatic disease, and CMV reactivation can lead to infections in granulomatosis with polyangiitis patients by inducing CD4+CD28- T cell and depressing naïve T cell populations.1-4Despite this evidence, the prognostic value of CMV reactivation for severe infections in patients with connective tissue disease are still unknown.Objectives:The aim of this study was to examine prognostic factors for severe infection during the early phase of treatment, especially in CMV reactivation, in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) who received initial high dose corticosteroid therapy (prednisolone > 0.8mg/kg/day).Methods:We analyzed the data of 88 consecutive hospitalized patients newly diagnosed with AAV at our hospital from January 2006 to March 2019 in this retrospective cohort study. There were 32 patients with CMV reactivation during remission induction therapy compared to 56 patients without CMV reactivation. CMV reactivation was defined by the detection of CMV pp65 antigen in blood samples, and CMV positive cells ≥ 5 per 3.0 × 105polymorphonuclear neutrophils (PMNs). The variable for severe infections within 180 days with apvalue < 0.1 in univariate analysis were selected for multivariate analysis using the Cox regression model. The positive predictive value (PPV) and positive likelihood ratio (PLR) of CMV reactivation for subsequent severe infections were also analyzed.Results:Patients with CMV reactivation, compared to those without, had a higher prevalence of MPO-ANCA, renal manifestation and renal impairment at diagnosis, received hemodialysis (HD), higher revised five factor score (FFS), older age, higher Birmingham Vasculitis Activity Score at diagnosis, and higher initial doses of corticosteroids (CS) at baseline. Revised FFS ≥ 2, renal involvement, high initial serum creatinine (≥ 1.5 mg/dl) at diagnosis, received HD, and CMV reactivation were associated with severe infections in the univariate analysis, although receiving cyclophosphamide or rituximab was not. Among these variables, CMV reactivation (Hazard ratio [HR] 3.50; 95% confidence interval [CI]: 1.22-10.10;p= 0.02) and high initial serum creatinine at diagnosis (HR 8.09; 95%CI: 2.00-32.73;p< 0.01) were independent risk factors for severe infections within 180 days. (Table 1) The PPV and PLR of CMV reactivation for subsequent severe infections were 35% and 1.91. When including higher initial serum creatinine, PPV and PLR for subsequent severe infections was 67% and 7.26.Table 1.Cox regression analysis for severe infections within 180 days.Univariate analysisMultivariate analysisPotential prognostic factorsHR (95% CI)P valueHR (95% CI)P valueAge ≥ 651.36 (0.48-3.71)0.580Male1.23 (0.50-3.04)0.648Past history of lung disease0.39 (0.11-1.36)0.140Past history of diabetes mellitus0.64 (0.15-2.77)0.550Lung involvement1.76 (0.67-4.62)0.254Renal involvement†3.68 (1.22-11.10)0.021Serum Cr ≥ 1.5 at diagnosis9.50 (3.40-26.49)< 0.0018.09 (2.00-32.73)0.003Hemodialysis4.85 (1.73-13.54)0.0030.96 (0.31-2.97)0.950BVAS ≥ 201.50 (0.59-3.81)0.393Revised FFS ≥ 24.40 (1.28-15.13)0.0180.83 (0.16-4.27)0.818MPSL pulse therapy1.16 (0.47-2.86)0.746Received CYC or RTX1.54 (0.55-4.27)0.409CMV reactivation5.10 (1.93-13.48)0.0013.50 (1.22-10.06)0.020† “Renal involvement” was excluded in the multivariate analysis to avoid multicollinearity.Conclusion:Our study shows that there should be focus on subsequent severe infections when CMV reactivation is detected during early phase of treatment, especially in renal-impaired patients with ANCA-associated vasculitis.References:[1]Gardiner BJ et al. Rheumatol Int. 2019;39:1229-40[2]Hung M et al. J Microbiol Immunol Infect. 2019;52:114-21.[3]Hanaoka R et al. Mod Rheumatol. 2012;22:438-45.[4]Morgan MD et al. Arthritis Rheum. 2011;63:2127-37.Disclosure of Interests:Daisuke Waki Speakers bureau: Mitsubishi Tanabe Pharma, AbbVie Inc, eisai Co,. Ltd, ONO PHARMACEUTICAL CO., LTD,, Keisuke Nishimura Speakers bureau: Mitsubishi Tanabe Pharma Corporation. Pfizer Inc. Kyowa Kirin Co., Ltd. Chugai Pharmaceutical Co., Ltd. ONO PHARMACEUTICAL CO., LTD. Japan Blood Products Organization. Kissei Pharmaceutical Co., Ltd. Astellas Pharma Inc. AYUMI Pharmaceutical Corporation. Eisai Co., Ltd. DAIICHI SANKYO COMPANY. Norvartis AG. Bayer AG. Sanofi K.K., Tomohiro Yoshida: None declared, Keiichiro Kadoba: None declared, Nozomi Tanaka: None declared, Hiroyuki Murabe: None declared, Toshihiko Yokota: None declared