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The present study was to investigate whether dihydroartemisinin (DHA), which is a highly effective and safe drug in the treatment of malaria, could be repurposed for the treatment of skin fibrosis and vascular dysfunction in systemic sclerosis (SSc).The value of DHA was determined using a bleomycin-induced model of skin fibrosis. mRNA transcriptome analysis was performed, and the targets of DHA on fibroblasts were identified. Immunofluorescence staining was used to identify dermal vessels undergoing endothelial-to-mesenchymal transition (EndoMT). Autophagic flux was detected by western blot and mRFP-GFP-LC3 adenovirus vector transfection.Both systemic and topical administration of DHA decreased dermal thickness and collagen deposition and alleviated EndoMT in bleomycin-induced skin fibrosis mice model. Treatment of human umbilical vein endothelial cells (HUVECs) with TGF-β1 resulted in the acquisition of the activation marker (α-SMA) and loss of endothelial markers (CD31 and VE-cadherin), a process that was restored by DHA. DHA significantly suppressed skin fibroblast activation and collagen-1 production mainly through regulating PI3K-Akt pathway. DHA also induced fibroblast autophagic flux and that autophagy dependently suppressed collagen-1 production.The results of the present study revealed that oral and topical DHA administration ameliorated tissue fibrosis and protected dermal blood vessels from bleomycin-induced EndoMT. Our study has elucidated the value of repurposing DHA for the treatment of SSc. Key Points • Oral or topical usage of DHA alleviated dermal fibrosis and EndoMT in bleomycin-induced skin fibrosis mice models. • DHA autophagy dependently inhibited fibroblast activation and collagen deposition via PI3K-ATK pathway. • DHA inhibited EndoMT of HUVECs induced by TGF-β1 by the downregulation of α-SMA and the upregulation of CD31 and VE-cadherin.

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease that can involve multiple organs or systems. Lupus nephritis (LN) is associated with high mortality and morbidity. However, plenty of patients do not respond to present treatment or relapse. Iguratimod (IGU) is a new small molecular, anti-rheumatic drug and has shown the potential for drug repurposing from rheumatoid arthritis (RA) to LN treatment. It has been approved for treating RA in northeast Asia. Beyond expectation in a recent observational study, over 90% of thirteen refractory LN patients responded to iguratimod monotherapy in 24 weeks, with no steroids dose increasing or any other medication add-on during the entire follow-up.Methods/designThis study is a multi-center, randomized, 52-week parallel positive drug-controlled study. The study was designed as a head-to-head comparison between the iguratimod and present first-line therapy on LN patients. A total of 120 patients (60 patients each group) is in the enrolling plan. All enrolled patients are assigned randomly into trial and control groups. The patients will be selected from six study sites in China and will all have biopsy-proven active lupus nephritis. In the first 24 weeks of the trial, IGU is compared with cyclophosphamide as an induction therapy, and in the second 24 weeks, IGU is compared with azathioprine as a maintenance therapy. The primary outcome is renal remission rate including both complete remission and partial remission at week 52, which will be analyzed using a non-inferiority hypothesis test.DiscussionMost patients diagnosed with SLE will develop LN within 5 years and LN remains a major cause of morbidity and death for SLE patients. Although some medications are proven effective for the treatment of this condition, at least 20–35% LN patients have to suffer from relapse or ineffective treatment and medication intolerance is also frequent. This trial is designed to demonstrate whether iguratimod can be used as an alternative induction or maintenance therapy in subjects who have lupus nephritis. Data from this study will provide an evidence on whether or not iguratimod should be recommended to active LN patients.Trial registrationClinicalTrials.govNCT 02936375. Registered on October 18, 2016.

Objectives: To investigate whether cytomegalovirus (CMV) infection plays a role in the pathogenesis and prognosis of idiopathic inflammatory myopathy (IIM), particularly in anti-MDA5 antibody-positive (anti-MDA5+) dermatomyositis (DM).Methods: A prospective cohort of 204 newly diagnosed IIM patients and 50 healthy individuals were enrolled in the study. CMV-IgM and CMV-IgG antibody concentrations and lymphocyte counts were analyzed. Differences in categorical data were compared using Fisher's exact test and the chi-square test. One-year survival rates were analyzed in MDA5+ DM patients with and without CMV infection.Results: In IIM patients, the median CMV-IgM level was significantly higher than in healthy controls (6 U/mL vs. 0 U/mL, p < 0.05) as was the median CMV-IgG level (114 U/mL vs. 105 U/mL, p < 0.05). The percentage of recent CMV infections in the MDA5+ DM group was much higher than it was in the MDA5− IIM group (19.1% vs. 7.0%, p = 0.009). MDA5+ DM patients with CMV DNA-emia had poorer 1 year survival than the CMV-DNA− group (33.3% vs. 86.3%, p = 0.010). CMV-IgM-positive (CMV-IgM+) MDA5+ DM patients had lower CD4+ T cell counts (245.7 cells/μL vs. 420.5 cells/μL, p < 0.05) and CD19+ B cell counts (97.3 cells/μL vs. 240.6 cells/μL, p < 0.05).Conclusion: The number of CMV infections was significantly higher in IIM patients, particularly in MDA5+ DM patients. Lower CD4+ T cells and CD19+ B cells were observed in CMV-IgM+ MDA5+ DM patients. CMV infection may have an important role in the pathogenesis and prognosis of MDA5+ DM by disrupting immunity.

Objectives This study reports a low dose combination therapy of cyclophosphamide (CYC) and pirfenidone (PFD) and the efficiency and safety of the therapy in refractory connective tissue disease associated interstitial lung disease (CTD-ILD) patients. Patients and methods The study included seven CTD-ILD patients (2 males, 5 females; mean age 48.8 years; range, 32 to 63 years) treated between January 2016 and December 2017 in our clinic. At enrolment, all patients had shown no improvement in their symptoms (dyspnea or cough) after at least one month of high dose steroids treatment. Patients who had received adjusted immunosuppressive agents other than steroids or anti-fibrotic medications within the three months before enrolment were excluded. We changed the treatment to a low dose combination of CYC 0.4 g/m2 monthly and PFD 300 mg twice per day and quickly reduced the steroids. All the patients were followed-up for 12 months. Results Two patients had anti-synthetase syndrome, two had Sjogren syndrome, two had scleroderma and one had mixed connective tissue disease. The baseline forced vital capacity (FVC) was 39-81% and the six-minute walk distance (6MWD) was 202 m-324 m. Within 12 months follow-up, the median improvement in the FVC was 13.4% (range, 0-35.9%), the median improvement of carbon monoxide diffusing capacity was 6.3% (range, 1.7-16%) and the median improvement of 6MWD was 52.7% (range, 34.4-86.3%). All the patients were self-sufficient, and their dyspnea, chest high- resolution computed tomography scores, and quality of life improved simultaneously. Exceeding our expectations, no adverse events associated with CYC or PFD were observed during the follow-up period. Conclusion Our study provided preliminary while promising clinical evidence for combination therapy of CYC-PFD for CTD-ILD. A low dose combination of CYC and PFD was unexpectedly well tolerated, with satisfactory effects in refractory CTD-ILD patients. Well-designed controlled studies are needed to further establish the safety and efficacy of this approach.

Background Idiopathic inflammatory myopathies (IIM) are associated with a significantly higher risk of opportunistic infections including Pneumocystis jirovecii pneumonia (PJP), a potentially fatal opportunistic infection. However, no prior studies have evaluated PJP infection in subtypes of IIM. Objectives To investigate the prevalence and mortality rate of PJP infection in subgroups of IIM patients stratified according to myopathy-specific antibodies. Methods In the first part of the study, 463 consecutive patients with IIM were prospectively followed for a period of at least 1 year to analyze the incidence of PJP. In the second part of the study, we enrolled 30 consecutive PJP patients with any rheumatic disease in order to identify the mortality rate and risk factors by Cox regression analysis. The Kaplan-Meier method with log-rank testing was used to assess differences in survival. Results The prevalence of PJP in IIM patients was found to be 3.0/100 person-years, while in MDA5+ DM patients it was 7.5/100 person-years and in MDA5− IIM patients 0.7/100 person-years (P < 0.05). PJP typically occurred in the first 2 months in the case of MDA5+ DM patients who had a significant decrease in their CD4+ T cell counts and lymphocyte counts (P < 0.05). In PJP patients, 3-month mortality was higher for MDA5+ DM patients than in those with other rheumatic diseases (83.3% vs 38.9%, P < 0.05). Alarmingly, MDA5+ DM patients seemed not to benefit from prompt anti-PJP treatment, unlike patients with other rheumatic diseases whose survival improved when anti-PJP treatment was started within 6 days (P < 0.05). Conclusion PJP has an alarming high incidence and mortality in MDA5+ DM patients. Timely treatment for PJP seems not to improve the prognosis of patients with this particular subtype. Hence, there remains a crucial unmet need to develop PJP prophylaxis for MDA5+ DM patients.

Over the years, our perceptions of fibrogenesis in systemic sclerosis (SSc) have advanced a lot. Herein, we review potential targets for SSc discovered in the past 3 years. In recent years, metabolites have come into the limelight of SSc research. Anti-oxidants, promotor of adipogenesis, modulator of fatty acid metabolism, regulator of glucose homeostasis, and adenosine deaminase open a new door for SSc treatment. A mosaic of biolipids, especially cannabinoid receptor 2 agonist, represents a rational therapeutic approach in fibrosis. In terms of immune aspects, targeting chemokines or integrins for cell adhesion may become new approach to inhibiting fibrotic pathways. Epigenetic modulation of immune pathways has been uncovered much recently. Targeting histone modifications and lncRNAs has demonstrated therapeutic potential in SSc animal models. The classical JAK-STAT and interferon pathway drive great attention these years because of the promising potential for the drug repurposing of targeted therapies from arthritis to SSc. In fibrosis-associated developmental pathways, BMP, Hedgehog, and PU.1 are expected to offer new targets to restrain fibrosis. New targets involved in metabolic reprogramming, immunity, epigenetics together with developmental and apoptotic pathways open new avenues for therapeutic modulation in SSc.

Objectives Iguratimod, a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective against murine lupus. The aim of this study was to make a preliminary evaluation of the efficacy and safety of iguratimod as salvage therapy in patients with refractory lupus nephritis (LN). Methods We enrolled eligible patients with refractory LN, which we defined as having failed or relapsed on at least two immunosuppressant agents. After enrollment, we substituted iguratimod (25 mg twice daily) for their previous immunosuppressant agents without increasing the dose of steroids. The primary outcome was complete/partial remission (PR/CR) at week 24. Patients who achieved remission continued iguratimod as maintenance therapy over an extended follow-up. Results The study cohort comprised 14 patients with refractory LN, 10 of whom had recent treatment failure and 4 repeated relapses with inadequate initial responses. At enrollment, none of the patients had detectable evidence of extra-renal involvement. The median prednisone dosage was 10 mg/d (IQR 0–10 mg/day). Thirteen patients were eligible for response evaluation, with one patient missed. The renal response rate was 92.3% (12/13) at week 24, with 38.5% (5/13) achieving CR and 53.8% (7/13) achieving PR. We then continued to follow up the responding patients for up to 144 weeks. Twenty-five percent of the patients (3/12) had renal relapse after initial PR. The estimated glomerular filtration rate of all patients maintained stable during follow-up. One patient had a severe adverse reaction (anemia) but recovered fully after stopping iguratimod. Conclusions Our study supports the potential of iguratimod for treatment of refractory LN. Iguratimod could be a promising candidate drug for this condition.

Background: Despite significant advances in the management of patients with lupus nephritis (LN), a significant proportion of patients either do not respond to first-line immunosuppressive drugs, or relapse after initial remission. Iguratimod is a novel disease modifying anti-rheumatic drug that has been approved for treating rheumatoid arthritis in East Asia and has shown benefits in lupus animal model in our previous research.(1) Objectives: The aim of the present study was to make a preliminary observation on the efficacy and safety of iguratimod in treating refractory LN patients. Methods: We have enrolled adult refractory LN patients who were eligible if they experienced at least two times of failure or relapse before enrollment. Failure was defined as no response to one certain immunosuppressive drug for at least six months. After enrollment, we simply switched their previous immunosuppressant to daily iguratimod (25 mg twice per day), while keeping all other medications. Complete/partial remission (PR/CR) was used as the primary outcome. 24h urine protein, blood cell counts, liver and kidney function were routinely monitored. Results: A total of 20 refractory LN patients had been enrolled (18 female and 2 male patients) since 2015. At enrollment, the median proteinuria was 2.588g/24h (range: 0.98-13.79g/24h). None of them had overt extra-renal involvement. All of them had biopsy-proven LN (class III/IV/V) and two patients agreed repeated biopsy before switching to iguratimod. The median prednisone dosage was 10mg/d (range: 5-35mg/d). One patient was lost to follow-up and one withdrew from the study. Of the remaining 18 patients, 16 patients achieved PR/CR and 2 did not respond to iguratimod. Of the 16 patients who achieved remission, 3 had renal relapse after initial PR and 1 had extra-renal flare after initial CR. One PR patient withdrew from the study due to severe anemia and another due to incompliance. For the remaining 10 patients who were still in follow-up, the median follow-up was 84 weeks (range: 28-144 weeks), with 4 having CR and 6 PR. The median response duration (MRD) was 12 weeks. Conclusion: Out study provided preliminary but promising clinical evidence for iguratimod in treating refractory LN patients. A large randomized clinical trial is needed to establish its safety and efficacy for refractory LN. References: [1] Yan Q, Du F, Huang X, Fu Q, Chen S, Dai D, et al. Prevention of immune nephritis by the small molecular weight immunomodulator iguratimod in MRL/lpr mice. PLoS One. 2014;9(10):e108273. Disclosure of Interests: None declared

Background There are anti-inflammation and anti-fibrosis agents available for connective tissue disease associated interstitial lung disease (CTD-ILD). A clinical study has been initiated to assess the combination of the two (NCT03221257), but whether they can spare dose for each other is unknown. Objectives This preliminary study is aimed to observe outcomes of CTD-ILD patients receiving cyclophosphamide plus pirfenidone as a rescue therapy, with each agent at about one third of routine dosage. Methods We enrolled CTD-ILD patients who did not improve their symptoms (dyspnea or cough) after at least one-month steroids treatment (prednisone≥1mg/kg daily). Patients who had adjusted immunosuppressive agents other than steroids or had received anti-fibrotic medications within three months before enrollment were ruled out. We switched the treatment into pulse cyclophosphamide (0.4g/m2 monthly) combined with pirfenidone (300mg twice per day). Besides, we reduced the steroids to prednisone 0.5mg/kg daily and then tapered routinely. All the patients were followed up for 12 months. Results We enrolled seven patients, of whom two had anti-synthetase syndrome, two had Sjogren syndrome, two had scleroderma and one had mixed connective tissue disease. The media DLCO was 51% of prediction (range47.7% to 63%) and media FVC was 72.3% of prediction (range 39% to 81%). The media 6MWD was 275m (range202 to 324m). At the end of 12-month follow-up, all the patients regained functional independence with a media 52.7% increase of 6-minute walk distance (range34.4% - 86.3%). Pulmonary function tests showed improved forced vital capacity (median improvement 13.4%, range 0-35.9%) and DLCO (median improvement 6.3%, range 1.7%-16%). The HRCT score had a median decrease of 20.1% (range 11.7% to 29.6%). For quality of life assessment, the SGRQ total score had a median improvement of 53.3% (range 19.5% to 61.7%). Of note, no adverse events were observed during the 12-month follow-up. Conclusion Our Study provided preliminary but promising clinical evidence for a new strategy in treating CTD-ILD, that cyclophosphamide and pirfenidone might work in synergy and spare dose for each other. A well-designed controlled study is needed to further establish its safety and efficacy. References None. Disclosure of interests None declared

Background Systemic sclerosis (SSc) is an autoimmune disease characterized with multiple organ fibrosis. Previous studies showed transcription factor early growth response 1 (Egr1) overexpressed in the lesional skin of SSc patients, as well as Egr1 inducible genes1. Egr1 forms a positive feedback loop with master pro-fibrotic cytokine TGF and thus promotes fibrosis. Objectives To investigate the anti-fibrotic effect of a novel DMARD iguratimod in scleroderma models and patient skin grafts. Methods We used iguratimod to treat TGF-stimulated human skin fibroblast, bleomycin induced mice, tight skin 1 (TSK-1) mice and SSc skin grafts. The bleomycin model contained pre-establish fibrosis and late onset treatment. The skin grafts came from three SSc patients and was planted into irradiated nude mice. Results Iguratimod down-regulated egr1 expression in human skin fibroblast, with decreased collagen production and a-SMA expression. Knocking down Egr1 in fibroblast could mimic these effects. Both oral and topical iguratimod could reduce dermal thickening and collagen deposition in bleomycin induced skin fibrosis. a-SMA (+) myofibroblast counts, as well as Egr1 (+) and/or TGF (+) fibroblast counts in iguratimod treated groups were significantly less than the controls. Similarly, topical iguratimod ameliorated fibrosis with deduced dermal thickening in TSK-1 mice. Of note, 5-week iguratimod local injection remarkably reduced collagen content in skin grafts from three SSc patients. Staining of Egr1 and TGF in skin tissue were inhibited after iguratimod treatment simultaneously. Conclusion We found the potential of iguratimod to treat SSc, which was characterized as an Egr1 inhibitor. Further clinical investigation is needed to establish its safety and efficacy. References [1] Bhattacharyya S, Sargent JL, Du P, et al. Egr-1 induces a profibrotic injury/repair gene program associated with systemic sclerosis. PloS one 2011;6(9):e23082 doi: 10.1371/journal.pone.0023082 [2] Chen SJ, Ning H, Ishida W, et al. The early-immediate gene EGR-1 is induced by transforming growth factor-beta and mediates stimulation of collagen gene expression. The Journal of biological chemistry 2006;281(30):21183-97 doi: 10.1074/jbc.M603270200 [2] Wu M, Melichian DS, de la Garza M, et al. Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing. The American journal of pathology 2009;175(3):1041-55 doi: 10.2353/ajpath.2009. Acknowledgement This work is supported by National Natural Science Foundation of China (81601401). Disclosure of Interests None declared

Background:Idiopathic inflammatory myopathies (IIM) was associated with a significantly higher risk of opportunistic infections that including Pneumocystis jiroveci pneumonia(PJP) which is potentially fatal opportunistic infection. However, no prior studies have evaluated the PJP infection in subtypes of IIM.Objectives:To investigate the incidence rate and mortality rate of PJP infection in subgroups of IIM patients according to myopathy specific antibodies.Methods:In the first part, we reviewed 463 consecutive patients with IIM retrospectively to analyze incidence of PJP infection. In the next part, we enrolled 30 consecutive PJP infection patients with any rheumatic disease was to identify the mortality rate and risk factors. Kaplan-Meier curve with log rank test was used to access differences in survival. Univariate and multivariate analyses were performed to identify prognostic factors using Cox regression.Results:We found that 12(7.5%) PJP cases occurred in 160 anti-MDA5-ab-positive DM patients, while only two (0.7%) PJP cases were found in 303 anti-MDA5-ab-negtive DM/PM patients(P < 0.05). PJP infection typically happened in the first two months of the treatment for anti-MDA5-ab-positive DM patients who have a significant decrease in the CD4+ T cell counts and Lymphocyte counts (P < 0.05). Only two (16.7%) anti-MDA5-ab-positive DM patients recover from PJP, with lethally higher mortality than those PJP infection with other rheumatic diseases (83.3% vs. 38.9%, P < 0.05). We found no association between the time to anti-PJP treatment and treatment outcomes in anti-MDA5-ab-positive DM; yet we confirmed in PJP infection with other rheumatic diseases that anti-PJP treatment within 6 days crucially increased the survival (P < 0.05).Conclusion:PJP infection has alarming high incidence and mortality in anti-MDA5-ab-positive DM patients. Unlike PJP infection with other rheumatic diseases, timely treatment for PJP doesn’t improve the prognosis of this particular subtype. Therefore, the necessity of further study of PJP prophylaxis treatment in anti-MDA5-ab-positive DM patients is verified.References:[1]Hsu CY, et al. Comparing the burdens of opportunistic infections among patients with systemic rheumatic diseases: a nationally representative cohort study. ARTHRITIS RES THER 2019, 21(1):211.Acknowledgements:The authors thank Dr. An Sun,Disclosure of Interests:None declared

This study aims to identify risk factors for thrombosis in patients with systemic lupus erythematosus (SLE) and to validate the efficacy of the partial antiphospholipid (aPL) score for thrombosis prediction and diagnosis of antiphospholipid syndrome (APS). This study included 325 SLE patients, 188 of whom completed a follow-up of 31.01 months (range 23-48 months). Partial aPL score was calculated by adding up the individual scores for activated partial thromboplastin time (APTT), lupus anticoagulant, IgG/IgM anticardiolipin antibodies (aCL), and IgG/IgM anti-β2-glycoprotein I (anti-β2GPI). A simplified aPL score was developed using only APTT, IgG/IgM aCL, and IgG/IgM anti-β2GPI. Partial aPL scores were significantly higher in SLE patients with thrombosis (p 0.0001). A history of thrombosis (p 0.0001), a partial aPL score10 (p 0.0001), and immunosuppressant use (p = 0.012) were independent risk factors for thrombosis. For patients with a history of thrombosis, partial aPL score was the strongest risk factor for recurrent thrombosis (p 0.0001, odds ratio = 30.34 (95 % CI 7.70-118.81)). For APS diagnosis, the area under the receiver-operating characteristic curve (AUC) was 0.809 (95 % CI 0.73-0.89) using the partial aPL score. Similarly, the simplified aPL score was significantly associated with thrombosis (p 0.0001) and was acceptable for APS diagnosis (AUC 0.797, 95 % CI 0.72-0.88). An elevated partial aPL score is a strong risk factor for thrombosis in SLE patients and is a useful tool to predict recurrent thrombosis. Partial aPL score and simplified aPL score, although comprising fewer items than the original aPL score, also represent valuable quantitative indices for APS diagnosis.

Background: In the SENSCIS trial in patients with SSc-ILD, nintedanib reduced the rate of decline in FVC over 52 weeks vs placebo, with no difference between groups in change in mRSS. Objectives: Analyse correlation between progression of skin fibrosis and progression of SSc-ILD in the SENSCIS trial. Methods: Patients with SSc-ILD were randomised to receive nintedanib or placebo until the last patient reached week 52 but for ≤100 weeks. We calculated Spearman correlation coefficients between FVC (mL) at baseline and change from baseline in mRSS, mRSS at baseline and change from baseline in FVC (mL), and changes from baseline in mRSS and FVC at weeks 52 and 100 in all patients. We analysed the rate of decline in FVC (mL/year) in patients who did and did not have progression of skin fibrosis (relative change from baseline in mRSS >25% and absolute change from baseline >5 points) at week 52. Results: In the nintedanib (n=288) and placebo (n=288) groups, respectively, mean (SD) baseline FVC (mL) was 2459 (736) and 2541 (816) and mRSS was 11.3 (9.2) and 10.9 (8.8); 53.1% and 50.7% had dcSSc;18.4% and 16.0% had progression of mRSS at week 52. No meaningful correlations were observed in analyses between mRSS and FVC (Table). The mean (SE) annual rate of decline in FVC in the placebo group was similar in patients who did and did not have progression of mRSS (-95.2 [27.1] and -91.4 [15.7] mL/year, respectively). The effect of nintedanib vs placebo on reducing the rate of decline in FVC was numerically more pronounced in patients who did not have progression of mRSS vs those who did (difference [95% CI] 44.3 mL/year [0.6, 88.1] vs 24.6 [-53.7, 102.9]), but the interaction p-value (0.66) did not indicate heterogeneity in treatment effect between subgroups. Conclusion: In the SENSCIS trial, the proportion of patients who had progression of skin fibrosis over 52 weeks was low, without significant differences between placebo and nintedanib. No meaningful correlations were observed between skin fibrosis at baseline or progression of skin fibrosis and progression of SSc-ILD. The rate of decline in FVC was similar between patients who did and did not have progression of mRSS. These findings suggest that in the overall patient population in the SENSCIS trial, progression of skin fibrosis and progression of ILD were distinct manifestations of disease progression. Disclosure of Interests: Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Kristin Highland Grant/research support from: Boehringer Ingelheim - PI for SENSCIS and SENSCIS-ON trials (paid to my institution), Consultant of: Kristin Highland has acted as a consultant to Boehringer Ingelheim. She was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Speakers bureau: Kristin Highland reports speaker fees from Boehringer Ingelheim, Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Otylia Kowal-Bielecka Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Inventiva, MSD, Novartis, Speakers bureau: Boehringer Ingelheim, Medac, Novartis, Roche, Sandoz, Ulrich Walker Grant/research support from: Ulrich Walker has received an unrestricted research grant from Abbvie, Consultant of: Ulrich Walker has act as a consultant for Abbvie, Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, MSD, Novartis, Pfizer, Phadia, Roche, Sandoz, Sanofi, and ThermoFisher, Paid instructor for: Abbvie, Novartis, and Roche, Speakers bureau: Abbvie, Actelion, Bristol-Myers Squibb, Celgene, MSD, Novartis, Pfizer, Phadia, Roche, Sandoz, and ThermoFisher, Francesco Del Galdo: None declared, Madelon Vonk Grant/research support from: Janssen and Ferrer, Consultant of: Boehringer Ingelheim, Janssen and GSK, Speakers bureau: Boehringer Ingelheim, BMS and Roche, Laura Hummers Grant/research support from: Boehringer Ingleheim, Corbus pharmaceuticals, CSL Behring, Cumberland Pharmaceuticals, and GlaxoSmithKline, Consultant of: Boehringer Ingleheim, Corbus pharmaceuticals, and CSL Behring, Elvira Erhardt Employee of: Employee of Boehringer Ingelheim, Manuel Quaresma Employee of: Employee of Boehringer Ingelheim, Margarida Alves Employee of: Employee of Boehringer Ingelheim, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl

Background and aims Previous studies found autophagy contributes to the pathogenesis of systemic lupus erythematosus (SLE). Whether autophagy is involved in lupus nephritis (LN) is not elucidated. P62 is a specific substrate that is degraded through autophagy-lysosomal pathway. Methods Immunohistochemistry Staining was performed to evaluate expressions of p62 in the biopsy kidney tissue of LN patients (n=128) and normal control (n=6). One hundred and five patients were given prednisone+CTX pulse therapy as induction treatment and followed by 24 weeks. Clinicopathologic features and induction phase remission efficacy were recorded and correlated with renal p62 expression level. Results Compared with the controls, the expression of p62 was significantly decreased in LN biopsy tissues (p=0.0013), suggesting increased autophagy in LN kidney. Patients with low expression of p62 had less severe nephritis, showing significantly less proteinuria, fewer interstitial fibrosis score and higher estimated creatinine clearance rates (p=0.0122, p=0.0048, p=0.0231, respectively). Logistic regression analysis revealed that lower renal p62 expression was an independent factor associated with CR(p=0.025) (Table 1). Patients with low p62 were more likely and quicker to achieve CR (Person Chi-Square test, p=0.001; Kaplan-Meier test, p=0.0294). Conclusions Low renal p62 expression was associated with less severe nephritis and better short-time outcome. Because low p62 expression is the result of high level of autophagy, this data suggested that autophagy might play a protective role in LN kidney. More studies are needed to evaluate the role autophagy plays in multiple organs and cell subtypes in SLE.

Background and Aims Iguratimod (IGT) is a small molecular immunomodulatory drug and has been approved for treating rheumatoid arthritis. In our previous work, IGT ameliorates lupus-like disease in MRL/ lpr mice by inhibiting abnormal B cell differentiation. The aim of this study is to further investigate the effects of IGT on human B cells. Methods We established a set of stimulations to induce naive human B cell into plasmablast (PB) in vivo . We also enrolled 7 patients with refractory lupus nephritis (LN) to assess the potential efficacy of IGT. Results IGT significantly attenuates the generation of CD19+CD20-CD27hiCD38hi plasma cells upon both BCR-dependent and independent stimulations. IGT affects neither proliferation or apoptosis of B cell in vitro . In further investigation on B cell differentiation signalling pathwasys, we identifies that Blimp-1 and Xbp-1 can be remarkably impaired by IGT both in transcriptional and protein level; while Jak/STAT or NF-κB signalling are intact with IGT treatment. For explosive clinical study, seven patients with refractory LN were enrolled and administrated with IGT and steroids. ALL of these patients surprisingly show improved proteinuria after 8 week treatment. One patient quit the treatment because of anaemia. Conclusions IGT has a unique effect to arrest B cell terminal differentiation, which provides strong evidence that this drug could be a new candidate drug to treat B cell related autoimmune diseases such as lupus.

Scleroderma is a refractory autoimmune skin fibrotic disorder. Alterations of microRNAs in lesional skin could be a new approach to treating the disease. Here, we found that expression of miR-155 was up regulated in lesional skin tissue from patients with either systemic or localized scleroderma and correlated with fibrosis area. Then we demonstrated the potential of miR-155 as a therapeutic target in pre-clinical scleroderma models. MiR-155−/− mice were resistant to bleomycin induced skin fibrosis. Moreover, topical antagomiR-155 could effectively treat mice primed with subcutaneous bleomycin. In primary skin fibroblast, miR-155 silencing could inhibit collagen synthesis function, as well as signaling intensity of two pro-fibrotic pathways, Wnt/β-catenin and Akt, simultaneously. We further showed that miR-155 could regulate the two pathways via directly targeting casein kinase 1α (CK1α) and Src homology 2-containing inositol phosphatase-1 (SHIP-1), as previous reports. Mice with miR-155 knockout or topical antagomir-155 treatment showed inhibited Wnt/β-catenin and Akt signaling in skin upon bleomycin challenge. Together, our data suggest the potential of miR-155 silencing as a promising treatment for dermal fibrosis, especially in topical applications.

The objective of this study is to assess serum IL8 and the potential activity of circulating neutrophils on relative messenger RNA (mRNA) levels and their relationship with disease activity in clinically amyopathic dermatomyositis (CADM) associated with interstitial lung disease (ILD). We studied 18 CADM patients and compared them with 18 classic dermatomyositis (DM) patients and 18 healthy control subjects. Serum IL8 level and mRNA expressions of neutrophils (chemokine (C-X-C motif) receptor 1 (CXCR1), cluster of differentiation molecule 11b (CD11b), cluster of differentiation 64 (CD64), myeloid cell leukemia 1 (MCL1), interleukin-18 (IL18)) were detected. The overproduction of serum IL8 level was most significant in the CADM group with active period. The mRNA expressions of CD11b, IL18, and MCL1 were greatly increased in the neutrophils in patients with CADM compared with DM or healthy controls. Up-expressions of CD11b, IL18, and MCL1 were detected in the neutrophils in CADM patients of active period compared with remission period. A positive correlation was found between CD11b mRNA level and high-resolution computed tomography (HRCT) score, in CADM associated with ILD. Serum IL8 level and mRNA levels of CD11b, MCL1, and IL18 in circulating neutrophils are related with the disease activity of CADM-ILD. The mRNA level of CD11b is positively correlated with HRCT score in CADM-ILD.

ObjectiveThis study was performed to investigate the therapeutic effects of iguratimod in a lupus mouse model.MethodsFemale MRL/lpr mice were treated with iguratimod, vehicle solution or cyclophosphamide. Proteinuria was monitored and kidney injury was blindly scored by a renal pathologist. Serum anti-double-stranded DNA antibodies were monitored by radioimmunoassay. Kidney IgG and CD20 were stained by immunohistochemistry. Splenic lymphocyte phenotypes were analyzed by flow cytometry. BAFF, IL-17A, IL-6, and IL-21 levels in serum and splenic lymphocytes were detected by ELISA or quantitative PCR.ResultsCompared with the vehicle-treated controls, MRL/lpr mice treated with iguratimod showed less protenuria, less acute pathological lesions and no chronic changes in the kidneys. There were significant differences in glomerular injury and vasculitis scores, as well as in the semi-quantitative analysis of immune complex deposition between the two groups. Disease activity markers in sera (anti-dsDNA antibodies and immunoglobulin levels) were reduced and hypocomplementemia was attenuated. Lymphocyte expression of BAFF, IL-6, IL-17A and IL-21 was decreased. The abnormal splenic B220+ T cell and plasma cell populations in MRL/lpr mice were reduced by iguratimod treatment, with recovery of the total B cell population and inhibition of B cell infiltration of the kidney tissue. The dosage of iguratimod used in this study showed no significant cytotoxic effects in vivo and no overt side-effects were observed.ConclusionIguratimod ameliorates immune nephritis in MRL/lpr mice via a non-antiproliferative mechanism. Our data suggest a potential therapeutic role of iguratimod in lupus.