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Additional file 1: Figure S1. Chronological G- and F-actin distribution in neutrophils stimulated by PMA. NETs were induced in peripheral blood neutrophils by 20 nM PMA. Before and 30 min, 1 h, and 3 h after incubation, the samples were fixed with 4% paraformaldehyde for 15 min and permeated with 0.5% Triton X-100 for 5 min at RT. Thereafter, the samples were reacted with 1:100 dilution of anti-β-actin mAb (mouse IgG1) at 4°C overnight. After rinsing with PBS, the samples were next reacted with 4 μg/mL Alexa Fluor 488-conjugated goat anti-mouse IgG1 antibody and 100 nM Acti-stain 555 phalloidin for 1 h at RT in the dark. The samples were finally mounted with the mounting solution containing DAPI. Anti-β-actin antibody recognizes G-actin, whereas phalloidin binds specifically to F-actin. Bar, 50 μm.

Objectives To evaluate the efficacy and safety of filgotinib for Japanese patients with rheumatoid arthritis (RA) and limited or no prior methotrexate (MTX) exposure. Methods Data up to 24 weeks were analysed for 71 Japanese patients from a 52-week global Phase 3 study. Patients with RA and limited or no prior MTX exposure were randomised in a 2:1:1:2 ratio to filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, or MTX. Maximum MTX dose was 15 mg/week. Primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at Week 24. Results Week 24 ACR20 rates in Japanese patients were 82.6%, 90.9%, 83.3%, and 80.0% for filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, and MTX, respectively. Greater ACR20 rates with filgotinib vs MTX occurred at Week 2. Greater proportions receiving filgotinib vs MTX achieved DAS28-CRP Conclusions While Week 24 ACR20 rates were similar, filgotinib provided faster responses and higher remission rates vs MTX. In Japanese patients with RA and limited or no prior MTX exposure, filgotinib was generally well tolerated.

Additional file 2. .

Additional file 1: Supplementary Figure 1. Relationship between serum MMP-3 and CXCL13 levels and clinical outcomes from 6 to 18 months in the RemIT-JAV-RPGN study. Supplementary Figure 2. Relationship between serum MMP-3 and CXCL13 levels and clinical outcomes in the MAAV-EU study.

Additional file 1: Table S1. Risk factors for total and treatment-related VDI. Table S2. Risk factors for hypertension, atrophy and weakness, cataract, and osteoporosis.

Additional file 2: Table S1. Clinical characteristics of EULAR responders vs moderate and non-responders at baseline.

Additional file 1: Figure S1A, B. Correlation between the IFN signature with 24 genes and the IFN signature with a smaller number of genes from the 24 genes. Figure S2. The receiver operating characteristics curve of the type I IFN score for the responders. (PPTX 65 kb)

Screening of marker candidates in serum samples from patients with AAV. Figure S2. Schematic diagram of targeted proteomics using the LC-SRM assay. Figure S3. Correlations between the light/heavy ratio of SRM and the ELISA titers of markers. Figure S4 Correlation of marker levels with total BVAS score of patients with AAV. Table S1. Clinical data on healthy donors and patients with RA, SLE, and infectious diseases. Table S3. Selected marker candidates for SRM assay development. Table S4. A set of established SRM transitions for the detection of marker candidates. Table S5. The 20 proteins with a significant change before and at 6 months after treatment in protocol 1 (n = 23) and protocol 2 (n = 29) in the SRM assay. Table S6. Comparison of serum levels of biomarker candidates between the remission group (n = 62) and the nonremission group (n = 17) at 6 months after treatment. Table S7. Marker levels in old healthy donors. Table S8. Comparison of serum levels of biomarker candidates between the patients with AAV with (n = 120) and without (n = 49) renal involvement before treatment. Table S9. Comparison of serum levels of biomarker candidates between the patients with AAV with and without lung involvement before treatment. Table S10. Comparison of marker levels among MPA, GPA, and EGPA before treatment. Table S11 Association of marker levels with disease severity in patients with AAV before treatment. (PDF 2221 kb)

Procedure of signature score calculation. (PDF 203 kb)

Enrichment plots of gene sets extracted from GSEA. (PDF 405 kb)

qRT-PCR results of five core genes of each signature identified from GSEA. (PDF 317 kb)

Illustration of the distribution of patients in this observational study. (PDF 223 kb)

Background Recent studies have investigated the pathogenesis of the class of conditions known as “other iatrogenic immunodeficiency-associated lymphoproliferative diseases” (OIIA-LPDs), particularly in patients with rheumatoid arthritis (RA). Methotrexate (MTX) is a potent cause of LPDs, and withdrawal of MTX can result in spontaneous regression of LPD, which suggests that this drug plays an important role in the tumorigenesis of LPDs. In addition, an impaired immunity against Epstein-Barr virus (EBV) has been obserbed in RA patients. A number of reports describe LPD regression in patients with OIIA-LPDs-RA, but its precise etiology and pathogenesis remain unclear. Furthermore, the phenomenon of relapse/regrowth of LPDs after initial regression has not been well documented. This study retrospectively analyzed the clinicopathological features of OIIA-LPDs-RA patients to determine the influence of EBV infection on regression/relapse of the disease. Methods & Results Data were collected from 35 patients with RA who developed LPD and who were treated at our institute between 1998 and 2013. All patients had received treatment with MTX. The diagnosis of RA was made according to the American College of Rheumatology criteria. Based on immunohistochemistry performed on paraffin-embedded tissue sections, diagnoses were as follows: diffuse large B cell lymphoma (DLBCL; n=14), Hodgkin lymphoma (HL; n=7), follicular lymphoma (FL; n=4), mucosal-associated lymphoid tissue (MALT; n=3), Hodgkin-like lymphoma (HL-like; n=3), T-cell lymphoma (n=3), polymorphic LPD (P-LPD; n=2) according to the 4th WHO classification. Regarding EBV infection, 16 patients (44%) were positive. Patients with FL, MALT, and T-cell lymphoma were negative for EBV, except for one patient with T-cell lymphoma. In contrast, EBV infection positivity was prevalent in patients with DLBCL, HL, HL-like and P-LPD (46%, 100%, 100%, and 50%, respectively). Although HL indicated a specific phenotype, such as positivity for CD15 and CD30 (83%, and 100%, respectively), and rarely expressed CD20, OCT2 or BOB1 (0%, 14%, 14%, respectively), the phenotypes of HL-like and P-LPD were supposedly intermediate between DLBCL and HL. The phenotypes of FL, MALT, and T-cell lymphoma were the same as those of de novo cases. LPD regression was observed in 23 (66%) of 35 patients, which is more common than that seen in previous reports. Although LPD regression was not documented in patients with T-cell lymphoma, it did occur in all patients with HL, HL-like and P-LPD. In addition, the incidence of regression among patients with DLBCL, FL and MALT was 46%, 75% and 33%, respectively. The relationship between EBV infection and LPD regression among patients with HL, DLBCL, HL-like and P-LPD was statistically significant (p=0.048, Fisher's exact test). Of 23 patients with regression, 13 patients (56%) subsequently showed relapse/regrowth, and the incidence of this phenomenon was relatively high in patients with HL, HL-like and P-LPD (100%, 67%, and 50%, respectively), whereas a lower incidence was seen in patients with DLBCL, FL, and MALT (7%, 33%, and 0%, respectively). Summary/Conclusions LPD regression was relatively common (66%) in patients with OIIA-LPDs-RA, particularly in patients with B cell phenotypes. There was a significant relationship between LPDs and EBV infection in patients with HL, DLBCL and HL-like, suggesting that underlying EBV infection might influence the immunosuppressant effect of MTX against EBV in those phenotypes. Further, LPD relapse/regrowth was common in patients with HL, HL-like and P-LPD and was unlikely in patients with DLBCL. Further studies would be of benefit to investigate the underlying molecular mechanism of regression/relapse of LPD after withdrawal of MTX. Disclosures: No relevant conflicts of interest to declare.