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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 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.

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.

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.

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: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

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

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 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.

Objective The canonical WNT pathway has been implicated as playing important roles in the pathogenesis of a variety of kidney diseases. Recently, WNT pathway activity was reported to be elevated in the renal tissue of a lupus mouse model. This study aimed to evaluate the potential role of the WNT pathway in the pathogenesis of human lupus nephritis. Methods The expression of β-catenin was evaluated in renal biopsy specimens from lupus nephritis patients and control kidney tissues by immunohistochemistry and western blotting. Real-time polymerase chain reaction (RT-PCR) was used to detect RNA expression of β-catenin, Dkk-1 and Axin2. Plasma concentrations of Dkk-1 were measured by ELISA. Results Immunohistochemistry and western blotting revealed increased expression of β-catenin in the kidneys of patients with lupus nephritis compared with control kidney tissues (p