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Rheumatoid factor (RF) binds to the fragment crystallizable (Fc) portion of immunoglobulin. It could bind to the Fc portion of anti-TNF inhibitors (TNFi) and attenuate the clinical efficacy. We tried to determine whether the therapeutic efficacy of TNFi with Fc might be lower than that of TNFi without Fc in rheumatoid arthritis (RA) patients with high titres of RF. The Kansai Consortium for Well-being of Rheumatic Disease Patients (ANSWER) cohort is an observational multi-center registry of patients with RA in the Kansai district of Japan. RA patients treated with TNFi were included and divided into two groups based on the structural characteristics between TNFi with Fc (infliximab, adalimumab, golimumab, and etanercept) and TNFi without Fc (certolizumab pegol). Patients were classified into 4 groups according to RF titre quartiles. The sequential disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) was compared by Mann-Whitney U test between TNFi with and without Fc in each RF titre group. Multiple linear regression analysis was used to analyze the effect of TNFi without Fc for the change of DAS28-ESR adjusted after potential confounders. A total of 705 RA patients were classified into four groups (RF

The aim of this multi-centre retrospective study was to clarify the prognostic factors for respiratory-related death in patients with interstitial lung disease (ILD) complicated rheumatoid arthritis (RA). Patient background data, treatment regimen, and disease activity indicators of RA and ILD at baseline, 6 months after the diagnosis of ILD, and at the last follow-up visit were extracted. A total of 312 patients with RA-ILD (17 patients who died from respiratory-related causes and 295 survivors) were included. Patients who died from respiratory-related causes had an older median age, a higher proportion of being male, and a higher anti-cyclic citrullinated peptide antibody positivity rate than survivors (p = .0001, .038, and .016, respectively); they also had significantly higher baseline serum levels of Krebs von den Lungen-6 (KL-6) than survivors (p = .013). Patients who died from respiratory-related causes showed significantly greater changes in serum KL-6 levels between the 6-month time point and the last visit [ΔKL-6 (6 months − last)] than survivors (p = .011). Multivariate analysis showed that the ΔKL-6 (6 months − last) corrected by disease duration was a predictor of respiratory-disease-related death in patients with RA-ILD (p

Objectives Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by localized and generalized bone loss. The risk of fractures is doubled in patients with RA. Denosumab, an anti-RANKL monoclonal antibody, is used for those with osteoporosis at high risk fracture and it has inhibitory effect of progressive bone erosion in patients with RA. While the increase in bone mineral density by denosumab has been reported in patients with RA, preventive effect of fracture by denosumab remains unknown. This study aimed to evaluate the efficacy of denosumab in treating clinical fracture risk in patients with RA. Methods Patients with RA who received denosumab treatment between 2013 and 2019 were retrospectively evaluated using the ANSWER (Kansai Consortium for the Well-Being of Rheumatic Disease Patients) cohort data. Fracture rates were evaluated between 0 and 6 months (reference period) versus > 6 months (post-reference period) of denosumab use. Results A total of 873 patients with RA received denosumab, and their characteristics were as follows: 88% females, mean age 68 years, and average disease duration 14.5 years. The hazard rates of all clinical fractures were 0.69 (per 100 person-years) in the reference period and 0.35 in the post-reference period, indicating a 49.2% decrease (p = 0.03). Conclusions Denosumab suppresses the risk of clinical fractures in patients with RA.

ObjectivesThis multicenter, retrospective study evaluated the effectiveness of add-on methotrexate (MTX) or iguratimod (IGU) in patients with rheumatoid arthritis exhibiting an inadequate response to Janus kinase inhibitors (JAKis).MethodsForty-five patients were treated with new additional MTX (n = 22) or IGU (n = 23) and followed for 6 months. Patients’ background is as follows: age, 59.2 years; disease activity score of 28 joints with C-reactive protein (DAS28-CRP), 3.4; clinical disease activity index, 15.7; biological disease-modifying antirheumatic drug (DMARD)-switched cases, 77.8%; first JAKi cases, 95.6%; and JAKi treatment: tofacitinib (n = 25), baricitinib (n = 17), upadacitinib (n = 2), and peficitinib (n = 1) for 9.6 months.ResultsThirty-five patients continued the combination therapy for 6 months without a significant change in concomitant glucocorticoid or other conventional synthetic DMARDs. DAS28-CRP (MTX, 3.6 to 2.6, p ConclusionsAdding MTX or IGU to inadequate responders of JAKi can be considered as a complementary treatment.

The objective of the study was to compare the efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) between elderly-onset rheumatoid arthritis (EORA) and young-onset rheumatoid arthritis (YORA) patients. Patients with rheumatoid arthritis (RA) aged ≧18 years enrolled in a Japanese multicenter observational registry between 2009 and 2018 who had moderate or high disease activity when initiating bDMARDs were included. EORA was defined as RA with onset at 60 or over. After propensity score weighting for differences in confounding factors, generalized estimating equations were used to assess the relationship between the age of RA onset and bDMARD clinical effectiveness at 48 weeks after starting a bDMARD. Among a total of 7183 patients in the registry, 2815 (39.2%) were identified as EORA. The proportion of patients on bDMARDs was lower in the EORA as compared to the YORA (18.3% vs 28.0%, p

The aim of this multicenter, retrospective study was to clarify the retention of secondary biological disease-modifying antirheumatic drugs (bDMARDs) or Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis (RA) who were primarily treated by tocilizumab (TCZ) or abatacept (ABT) as first bDMARDs.Patients who were treated by either TCZ (n = 145) or ABT (n = 76) and then switched to either tumor necrosis factor inhibitors (TNFi), TCZ, ABT, or JAKi (including only cases switched from TCZ) from 2001 to 2019 (female 81.0%, age 59.5 years, disease duration 8.8 years; rheumatoid factor positivity 75.4%; Disease Activity Score in 28 joints using C-reactive protein 3.7; concomitant prednisolone (PSL) dose 6.0 mg/day (51.8%) and methotrexate (MTX) dose 8.0 mg/week (56.1%); 81.9% discontinued first bDMARDs due to lack of effectiveness) were included. Drug retention and discontinuation reasons were estimated at 24 months using the Kaplan-Meier method and adjusted for potential confounders by Cox proportional hazards modeling.Drug retentions for each of the reasons for discontinuation were as follows: lack of effectiveness in TCZ-switched group (TNFi (59.5%), ABT (82.2%), and JAKi (84.3%); TNFi vs. ABT; P = 0.009) and ABT-switched group (TNFi (79.6%) and TCZ (92.6%); P = 0.053). Overall retention excluding non-toxic reasons and remission for discontinuation were TNFi (49.9%), ABT (72.7%), and JAKi (72.6%) (TNFi vs. ABT; P = 0.017) in the TCZ-switched group and TNFi (69.6%) and TCZ (72.4%) (P = 0.44) in the ABT-switched group.Switching to ABT in TCZ-treated patients led to higher retention as compared with TNFi. Switching to TCZ in ABT-treated patients tended to lead to higher retention due to effectiveness, although total retention was similar as compared with TNFi. Key Point • This is the first retrospective, multi-center study aimed to clarify the retention rates of secondary bDMARDs or JAKi in patients with RA who were primarily being treated by TCZ or ABT as the first bDMARDs.

Currently, biological disease-modifying anti-rheumatic drugs (bDMARDs) with different modes of action [tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), or cytotoxic T-lymphocyte antigen 4–immunoglobulin (CTLA4-Ig)] are used in clinical practice to treat rheumatoid arthritis (RA). However, it is unclear which type of bDMARD is the most efficacious for a specific clinical situation. C-reactive protein (CRP) is an acute-phase reactant driven by IL-6 signalling. Here, we aimed to establish whether therapeutic efficacy differs between IL-6Ri and other bDMARDs with alternative modes of action in RA patients according to their CRP level. RA patients treated with bDMARDs were enrolled from an observational multicentre registry in Japan. Patients were classified into three groups according to baseline CRP tertiles. The overall 3 year retention rates of each bDMARD category were assessed. The Clinical Disease Activity Index (CDAI) was also assessed before and 3, 6, and 12 months after bDMARD initiation. A total of 1438 RA patients were included and classified into three groups according to tertiles of baseline CRP levels (CRP1, 0–0.3; CRP2, 0.3–1.8; CRP3, 1.8–18.4 mg/dL). In CRP3, the overall 3 year drug retention rates were significantly higher for IL-6Ri than for TNFi and CTLA4-Ig (77.5 vs 48.2 vs 67.3, respectively). No significant difference was evident in terms of CDAI 12 months after bDMARD initiation in CRP1–CRP3. IL-6Ri may be a favourable therapeutic option over TNFi and CTLA4-Ig in RA patients with high CRP levels.

Background: This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) baricitinib (BAR) and tofacitinib (TOF) in patients with RA.Methods: Patients were included as follows: females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185) and concomitant glucocorticoid (prednisolone [PSL] equivalent) 5.3 mg/day (46.7%) or methotrexate (MTX) 8.9 mg/week (60.7%); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories: lack of effectiveness, toxic adverse events, non-toxic reasons and remission. The drug retention rate was estimated at 24 months using the Kaplan–Meier method and adjusted for potential confounders using multivariate Cox proportional hazards modelling.Results: Adjusted discontinuation rates for the corresponding reasons were as follows: lack of effectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior use of anti-interleukin-6 receptor antibody (aIL-6R) was significantly associated with discontinuation due to lack of effectiveness (P = 0.021). Ageing (P = 0.015), usage of PSL ≥5 mg/day (P = 0.017) and female sex (P = 0.041) were significantly associated with discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, different JAKi and prior use of TNF inhibitor, CTLA4-Ig or other JAKi.Conclusions: Prior use of aIL-6R was associated with discontinuation due to lack of effectiveness, while ageing (≥75 years), PSL usage ≥5 mg/day, and female sex were associated with discontinuation due to toxic adverse events.

Nobuyasu Ishii, Toshiki Shimizu, Yoshihisa Ishiura, Hideki Amuro, Tohru Nishizawa, Takeshi Tamaki, Shosaku Nomura First Department of Internal Medicine, Kansai Medical University, Moriguchi-City, Osaka, 570-8507, JapanCorrespondence: Toshiki ShimizuFirst Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi-City, Osaka, 570-8507, JapanTel + 81-6-6992-1001Fax + 81-6-6992-1066Email shimizto@takii.kmu.ac.jpBackground: Tocilizumab (TCZ) is humanized monoclonal antibody against the interleukin-6 (IL-6) and receptor that has prominent efficacy for the treatment of rheumatoid arthritis (RA). We conducted a retrospective observational study to determine how long TCZ controls RA.Patients and Methods: We retrospectively reviewed the medical records of RA patients treated with TCZ. The aim of this study was to evaluate the contribution of clinical parameters to disease control time (DCT) in RA patients.Results: Overall, 144 patients were enrolled in the study. The median age of patients was 66 years (range: 34– 85 years). In univariate analysis, DCT was significantly increased in patients who had never received previous biologic disease-modifying anti-rheumatic drugs treatment (P = 0.0064). We also analyzed the contribution of the base line value of C-reactive protein (CRP) to DCT. We divided the patients with RA into two groups according to a cutoff value of 1.000 mg/dl. The median control times were 77.5 months (95% confidence interval [CI]: 44.8–not reached to median) and 34.5 months (95% CI: 17.0– 79.3) for patients with high and low CRP value, respectively. In univariate analysis, DCT was significantly increased in patients with a high CRP value (P = 0.0283). Multivariate analysis clearly revealed that a high baseline CRP value was an independent favorable predictive factor for longer DCT (hazard ratio, 0.608, 95% CI: 0.378– 0.981, P = 0.0416).Conclusion: These data clearly demonstrate that the baseline value of CRP was closely associated with long time DCT in patients of RA treated with TCZ.Keywords: rheumatoid arthritis, tocilizumab, C-reactive protein, platelet large cell ratio, disease control time

A family history of rheumatoid arthritis (RA) is a strong risk factor for developing RA, affecting both genetically and environmentally. However, whether family history provides clinically relevant information in the modern classification and treatment remains largely unknown. This study aimed to determine whether a family history of RA is associated with a different clinical presentation of RA and treatment response. We retrospectively evaluated the demographic data and disease activity of newly diagnosed RA patients at baseline, 1 year, and 2 years after onset, using the ANSWER (Kansai consortium for the well-being of rheumatic disease patients) cohort data. Thirty-one patients (11.9%) among 260 newly diagnosed RA patients had a family history of RA up to second degree. There was no significant difference in the age at onset, time from onset to first visit, sex, positivity or value of rheumatoid factor or anti-cyclic citrullinated peptide antibody (ACPA), or disease activity between patients with and without a family history of RA. However, patients who had a family history of RA and were ACPA positive showed significantly lower erythrocyte sedimentation rate, and C-reactive protein. Disease activity in patients with a family history was not worse at baseline, after 1 year or 2 years of treatment. The Larsen score 2 years after onset was equivalent between the patients with and without a family history of RA in ACPA-positive patients. Family history of RA in ACPA-positive patients is not associated with high disease activity at baseline and is not a predictor of poor outcome 2 years after onset.

Sensing self-nucleic acids through toll-like receptors in plasmacytoid dendritic cells (pDCs), and the dysregulated type I IFN production, represent pathogenic events in the development of the autoimmune responses in systemic lupus erythematosus (SLE). Production of high-mobility group box-1 protein (HMGB1) promotes type I IFN response in pDCs. To better understand the active pathogenic mechanism of SLE, we measured serum levels of HMGB1, thrombomodulin, and cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17A, IL-17F, IFNα, IFNγ, TNFα) in 35 patients with SLE. Serum HMGB1 and IFNα were significantly higher in patients with active SLE (SLE Disease Activity Index (SLEDAI) score ≥ 6) compared with healthy donors or patients with inactive SLE. Furthermore, the HMGB1 levels were significantly correlated with IFNα levels. By qualitative analysis, the detection of serum IFNα or HMGB1 suggests active SLE and the presence of SLE-related arthritis, fever, and urinary abnormality out of SLEDAI manifestations. Collectively, HMGB1 and IFNα levels are biomarkers reflecting disease activity, and qualitative analysis of IFNα or HMGB1 is a useful screening test to estimate SLE severity and manifestations. Our results suggest the clinical significance of type I IFNs and HMGB1 as key molecules promoting the autoimmune process in SLE.

Background This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of either tumor necrosis factor inhibitors (TNFi) or interleukin-6 inhibitors (IL-6i) in patients with elderly-onset rheumatoid arthritis (EORA). Methods Patients with rheumatoid arthritis (RA) enrolled in a Japanese multicenter observational registry between 2011 and 2020 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding by indication for treatment with TNFi or IL-6i, a propensity score based on multiple baseline characteristics variables was used to compare the drug retention and causes for discontinuation between TNFi and IL-6i. Adjusted cumulative incidence of drug discontinuation for each reason was compared between the two groups using the Fine-Gray model. Results Among a total of 9,550 patients in the registry, 674 TNFi and 297 IL-6i initiators with EORA were identified. Age, the proportion of females, disease duration, and baseline disease activity at the time of TNFi or IL-6i initiation were similar between the two groups. After adjusting for differences in baseline characteristics between the two groups, overall drug discontinuation was significantly lower in the IL-6i as compared to the TNFi (HR = 0.71, 95%CI = 0.59–0.86, p p p = 0.28) or achievement of clinical remission (HR = 1.09, 95%CI = 0.62–1.91, p = 0.76) were similar between the two groups. Conclusions In EORA patients initiating a TNFi or IL-6i, significantly higher drug retention was observed with IL-6i. Discontinuation due to lack of effectiveness was significantly less frequent in IL-6i while discontinuations due to adverse event or achievement of clinical remission were similar between the two groups.

We aimed to investigate the efficacy of anti-IL-6 receptor antibody (aIL-6) and other biologic disease-modifying antirheumatic drugs (bDMARDs), such as TNF inhibitor and CTLA4-Ig in the treatment of rheumatoid arthritis (RA) in patients with knee joint involvement. We retrospectively analyzed 1059 treatment courses of patients with RA who visited our hospitals and were treated with bDMARDs. We categorized them into two groups, with or without knee joint involvement. We investigated the clinical disease activity index (CDAI) at baseline and 12 weeks after the initiation of bDMARDs. We compared the improvement of the markers between aIL-6 and other bDMARDs. Treatment with aIL-6 significantly increased ΔCDAI (n = 91, 15.4 ± 1.1; mean ± SEM) in patients with knee joint involvement, compared to other bDMARDs (n = 232, 11.0 ± 0.7) at 12 weeks (P = 0.006). Following the multivariate analysis adjusted by the CDAI levels at baseline, age, gender, concomitant use of methotrexate, and the first use of bDMARDs, ΔCDAI levels were significantly higher in aIL-6, compared to other bDMARDs (P = 0.02). However, there was no significant difference in ΔCDAI improvement between aIL-6 (n = 162, 5.9 ± 0.6) and other bDMARDs (n = 573, 6.2 ± 0.4) in patients without swollen knee joints. ΔCDAI levels were equally increased in patients with shoulder and elbow joint involvement. aIL-6 was more effective in the patients with RA and knee joint involvement, compared to other bDMARDs.

Background: This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of either Tumor Necrosis Factor inhibitors (TNFi) or Interleukin-6 Inhibitors (IL-6i) in patients with elderly-onset rheumatoid arthritis (EORA).Methods: Patients with rheumatoid arthritis (RA) enrolled in a Japanese multicenter observational registry between 2011 and 2020 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding by indication for treatment with TNFi or IL-6i, a propensity score based on multiple baseline characteristics variables was used to compare the drug retention and causes for discontinuation between TNFi and IL-6i. Adjusted cumulative incidence of drug discontinuation for each reason was compared between the two groups using the Fine-Gray model. Results: Among a total of 9550 patients in the registry, 674 TNFi and 297 IL-6i initiators with EORA were identified. Age, the proportion of females, disease duration, and baseline disease activity at the time of TNFi or IL-6i initiation were similar between the two groups. After adjusting for differences in baseline characteristics between the two groups, overall drug discontinuation was significantly lower in the IL-6i as compared to the TNFi (HR=0.71, 95%CI=0.59-0.86, p

The aim of this multicenter, retrospective study was to clarify the retention rates of sarilumab (SAR), baricitinib (BAR), and tofacitinib (TOF) in patients with rheumatoid arthritis (RA).Patients treated with either SAR (n = 62), BAR (n = 166), or TOF (n = 185) (females, 80.9%; age, 61.0 years; disease duration, 11.1 years; rheumatoid factor positivity, 84.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone dose, 5.3 mg/day [47.0%] and methotrexate dose, 8.8 mg/week [58.4%]; biologics- or Janus kinase inhibitors-switched cases 78.4%) were included. The reasons for drug discontinuation were classified into 4 major categories (lack of effectiveness, toxic adverse events, non-toxic reasons, and remission) by each attending physician. The drug retention rate was estimated at 18 months using the Kaplan-Meier method and adjusted for potential confounders by Cox proportional hazards modeling.The discontinuation rates of SAR, BAR, and TOF for the corresponding reasons were as follows, respectively: lack of effectiveness (15.7%, 15.6%, and 21.5%; P = 0.84), toxic adverse events (15.8%, 12.1%, and 12.3%; P = 0.35), non-toxic reasons (10.9%, 7.7%, and 6.8%; P = 0.35), and remission (0.0%, 2.8%, and 0.0%; P = 1.0). The overall retention rates excluding non-toxic reasons and remission were as follows: 68.8% for SAR, 72.5% for BAR, and 66.7% for TOF (P = 0.54).After adjustment by potent confounders, SAR, BAR, and TOF showed similar discontinuation rates due to lack of effectiveness and toxic adverse events. Key Points • This is the first retrospective multicenter study that aimed to clarify the retention rates and reasons for discontinuation of SAR, BAR, and TOF in patients with RA.

Background: Rheumatoid factor (RF) binds to the Fc portion of immunoglobulin and can bind to the Fc portion of anti-TNF monoclonal antibodies (TNFi), attenuating their clinical efficacy. We tried to determine whether the therapeutic efficacy is different between TNFi with or without the immunoglobulin Fc portion in rheumatoid arthritis (RA) patients depending upon the RF titres.Methods: RA patients treated with TNFi were enrolled from an observational multi-centre registry in Japan. TNFi treatments were divided into two groups based on the structural characteristics between TNFi with Fc (infliximab, adalimumab, golimumab, etanercept) and TNFi without Fc (certolizumab-pegol). Patients were classified into 4 groups according to RF titre quartiles. The sequential disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) were compared by the Mann-Whitney U test between TNFi with and without the immunoglobulin Fc portion in each RF titre group.Results: A total of 705 RA patients were included and classified into four groups according to quartiles of baseline RF titres (RF1; RF 0-15.0 IU/mL, RF2; 15.0-55.0, RF3; 55.0-166, RF4; 166-7555). In RF4, RA patients treated with TNFi without Fc had a significantly lower DAS28-ESR than those treated with TNFi with Fc (3.2 (2.3-4.2) vs. 2.7 (2.0-3.0)) (median, IQR) after 12 months of follow-up, while there were no significant differences in RF1, RF2, and RF3.Conclusion: TNFi without Fc (certolizumab-pegol) may be more efficacious than TNFi with Fc in RA patients with high RF titres.

BackgroundBoth humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs.MethodsWe isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-α production.ResultsWe found that treatment with 1−10 μM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs.ConclusionsOur data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

BackgroundBoth humoral and cellular immune mechanisms are involved in the onset and progression of the autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLEvia the dysregulation of type I interferon (IFN) production;these cells act together with activated myeloid DCs (mDCs), to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of the aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMFin targeting DC functions, especially the IFN response of pDCs.MethodsWe isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-a production.ResultsWe found that treatment with 1-10mM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs(but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation in pDCsand IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs.ConclusionsOur data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disordersby regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

Background The aim of this study is to evaluate the retention rates and reasons for discontinuation for seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). Methods This multi-center, retrospective study assessed 4466 treatment courses of 2494 patients with bDMARDs from 2009 to 2017 (females, 82.4%; baseline age, 57.4 years; disease duration 8.5 years; rheumatoid factor positivity 78.6%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone (PSL) 2.7 mg/day (43.1%) and methotrexate (MTX) 5.0 mg/week (61.8%); and 63.6% patients were bio-naïve). Treatment courses included tocilizumab (TCZ; n = 895), etanercept (ETN; n = 891), infliximab (IFX; n = 748), abatacept (ABT; n = 681), adalimumab (ADA; n = 558), golimumab (GLM; n = 464), and certolizumab pegol (CZP; n = 229). Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential confounders (age, sex, disease duration, concomitant PSL and MTX, and switched number of bDMARDs) using Cox proportional hazards modeling. Results A total of 56.9% of treatment courses were stopped, with 25.8% stopping due to lack of effectiveness, 12.7% due to non-toxic reasons, 11.9% due to toxic adverse events, and 6.4% due to disease remission. Drug retention rates for each discontinuation reason were as follows: lack of effectiveness [from 65.5% (IFX) to 81.7% (TCZ); with significant differences between groups (Cox P

Systemic amyloid A (AA) amyloidosis secondary to rheumatoid arthritis (RA) is a serious complication, often leading to end-stage renal disease (ESRD) or death. Intervention with biologic agent, which has brought a paradigm shift in the treatment of RA, may improve the prognosis of AA amyloidosis. Among RA patients in ANSWER Cohort in Japan, 11 patients with biopsy-proven AA amyloidosis were identified and retrospectively investigated. Median age at the diagnosis of AA amyloidosis was 64 years and median disease duration of RA was 16 years. ESRD occurred in 5 patients, and 3 of them died. Seven patients received the treatment with biologic agents. Poor prognosis such as ESRD or death was associated with advanced renal dysfunction, insufficient anti-inflammatory treatment and longer disease duration of RA, whereas good prognosis was associated with no renal involvement or mild renal dysfunction, and the use of biologic agents. This observation, along with presentations of all identified cases, suggests the importance of disease control during mild kidney damage using potent anti-inflammatory drug such as biologic agent to improve prognosis..

Background:A number of previous reports suggested that obesity is one of the baseline factors indicates refractory to biologic disease-modifying antirheumatic drugs (bDMARDs). However, difference of the significant responses appears on obesity patients depending on each kind of drug is yet unclear. However, it is yet unclear how the significant responses on obesity patients vary on each kind of drug.Objectives:To assess whether obesity affects clinical outcome in rheumatoid arthritis (RA) treated with each molecular-targeted agent including bDMARDs and tofacitinib.Methods:In Kansai consortium for well-being of rheumatic disease patients (ANSWER) cohort, which was the real-world retrospective cohort of clinical database for rheumatic diseases, RA patients who initiated biological / targeted disease modifying anti-rheumatic drugs were included and consecutively followed. Obesity was defined as BMI over than 25, and patients were divided between obese (“Ob”) and non-obese (“non-Ob”) patients. SDAI (simplified disease activity index) was compared between non-Ob and Ob at month 0, 3, 6, 9, 12 after the indicated drugs were administered. Using logistic regression analysis, odds ratio (OR) and their corresponding 95% confidence intervals (95% CIs) were further calculated to estimate achievement rate of SDAI remission defined as lower than 3.3 by obesity and other relevant clinical parameters. Once after the drugs were discontinued by any unfavorable reason, disease activities were no more scored and the Last Observation Carried Forward (LOCF) imputation method was used for SDAI at month 3 and thereafter.Results:A total of 1936 patients met in the inclusion criteria were under the analysis. In each drug, SDAI remission rate (non-Ob, Ob, p-value by Chi-square test) at month 12 was as follows; Infliximab (IFX, n=135): 43%, 38%, NS (not significant); Etanercept (ETN, n=188): 44%, 19%, p=0.0122; Adalimumab (ADA, n=169): 50%, 56%, NS; Golimumab (GLM, n=315): 36%, 30%, NS; Certolizumab pegol (CZP, n=131): 33%, 56%, p=0.0287; Tocilizumab (TCZ, n=423): 41%, 29%, p=0.0456; Abatacept (ABT, n=144): 26%, 23%, NS; Tofacitinib (TOF, n=69): 27%, 23%, NS. In multivariate analysis to predict SDAI remission at month 12, obesity was an independent protective factor in CZP (OR: 0.29, 95% CIs: 0.10 – 0.83), but was an independent risk factor in TCZ (OR: 1.9, 95% CIs: 1.01 – 3.61) irrespective of age, sex, disease duration, SDAI at month 0 or number of previous bDMARDs. Any other drug including ETN did not show significant result between non -Ob and Ob in the multivariate analysis.Conclusion:Obese patients were more resistant to TCZ but more effective in CZP than non-obese patients.References:[1]Ann Rheum Dis. 2018;77(10):1405-1412. Joint Bone Spine. 2019;86(2):173-183.Disclosure of Interests:Kosaku Murakami Speakers bureau: AbbVie, Eisai, and Mitsubishi Tanabe Pharma., Motomu Hashimoto Grant/research support from: Bristol-Myers Squibb, Eisai, and Eli Lilly and Company., Speakers bureau: Bristol-Myers Squibb and Mitsubishi Tanabe Pharma., Koichi Murata Grant/research support from: KMurata belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan)., Employee of: KMurata belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan)., Speakers bureau: KMurak has received speaking fees, and/or consulting fees from Eisai Co. Ltd, Chugai Pharmaceutical Co. Ltd., Pfizer Japan Inc, Bristol-Myers Squibb, Mitsubishi-Tanabe Pharma Corporation, UCB, Daiichi Sankyo Co. Ltd. and Astellas Pharma Inc., Wataru Yamamoto: None declared, Ryota Hara Speakers bureau: RH received a speaker fee from AbbVie, Masaki Katayama: None declared, Akira Onishi Speakers bureau: AO received a speaker fee from Chugai, Ono Pharmaceutical, Eli Lilly, Mitsubishi-Tanabe, Asahi-Kasei, and Takeda, Kengo Akashi: None declared, Koji Nagai: None declared, Yonsu Son: None declared, Hideki Amuro: None declared, Toru Hirano Grant/research support from: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Speakers bureau: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Kosuke Ebina Grant/research support from: KE has received research grants from Abbie, Asahi-Kasei, Astellas, Chugai, Eisai, Ono Pharmaceutical, and UCB Japan., Employee of: KE is affiliated with the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho., Speakers bureau: KE has received payments for lectures from Abbie, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Sanofi, and UCB Japan., Kohei Nishitani Grant/research support from: KN belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan)., Masao Tanaka Grant/research support from: AbbVie, Asahi Kasei Pharma, Astellas Pharma, Ayumi Pharmaceutical, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Taisho Pharmaceutical, and UCB Japan., Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly and Company, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Novartis Pharma, Pfizer, Taisho Pharmaceutical, Takeda Pharmaceutical, and UCB Japan., Hiromu Ito: None declared, Koichiro Ohmura Grant/research support from: Astellas Pharma, AYUMI Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Japan Blood Products Organization, Mitsubishi Tanabe Pharma, Nippon Kayaku, Nippon Shinyaku, Sanofi, and Takeda Pharmaceutical., Speakers bureau: AbbVie, Actelion Pharmaceuticals Japan, Asahi Kasei Pharma, AYUMI Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Novartis Pharma, and Sanofi.

Background:It has been reported that rheumatoid arthritis (RA) patients who have large joint involvement associated with higher serological inflammatory markers and more functional disability1. Moreover, a previous report showed that these patients were more difficult to achieve clinical remission. However, it remains unclear which biologics are effective in the patients with RA who have large joint involvement.Objectives:The aim of this study is to investigate the efficacy of anti-IL-6 receptor antibody (aIL-6) or TNF-inhibitor (TNFi) in the treatment of RA patients who have knee joint involvement.Methods:We enrolled the 784 patients who visited our hospitals in 2003 to 2019 and were treated with aIL-6 or TNFi more than 12 weeks. We divided the patients into 2 groups with or without knee joint involvement for further analysis. Knee joint involvement was defined as the patients had at least one swelling joint of knee at baseline. We investigated the CDAI levels at baseline and 12 weeks after the initiation of biologics.Results:Interestingly, the patients who had knee joint involvement with aIL-6 significantly ameliorated ΔCDAI (n=95, 15.0±10.8; mean±SD) compared to those with TNFi (n=148, 11.4±10.3) at 12 weeks (P=0.003). aIL-6 group consists of 95 tocilizumab treated patients. TNFi group includes 25 adalimumab, 25 certolizumab pegol, 14 etanercept, 54 golimumab and 30 infliximab treated patients. Baseline clinical characteristics of the 243 RA patients who had knee joint involvement were shown in Table 1. Mean ages, sex and disease durations were not significantly different between the two groups. Baseline CDAI levels of aIL-6 group (24.8±11.8) were slightly elevated compared to those of TNFi group (21.7 ±10.9). Multivariate analysis adjusted for age, gender and baseline CDAI levels revealed that aIL-6 significantly improved ΔCDAI levels compared to TNFi (P=0.04). By contrast, in the RA patients who had no swelling of knee joints, there was no significant difference of ΔCDAI improvement between aIL-6 group (n=156, 5.5±7.4) and TNFi group (n=385, 6.7±8.9).Table 1.Baseline clinical characteristics of 243 RA patients who had knee joint involvementaIL-6 group(n=95)TNFi group(n=148)p ValueAge (mean±SD)60.7±15.261.9±14.40.58Gender (female, %)80.079.10.97Duration (year)9.3 ±10.38.4±10.50.56DAS28ESR (mean±SD)5.3±1.25.2 ±4.80.03CDAI (mean ±SD)24.8±11.821.7 ±10.90.04MTX use, (%)45.462.20.02MTX dose (mg/day)8.7 ±3.39.0 ±3.50.61PSL use, (%)44.345.60.74PSL dose (mg/day)5.5 ±3.55.1 ±2.90.55Conclusion:Thus, these findings suggest that anti-IL-6 receptor antibody was more effective in the RA patients with knee joint involvement compared to TNF- inhibitor.References:[1]Burgers LE, et al.Ann Rheum Dis. 2018;77:e33.Disclosure of Interests:Yuichi Maeda Grant/research support from: YM received a research grant and/or speaker fee from Eli Lilly, Chugai, Pfizer, Bristol-Myers Squibb, and Mitsubishi-Tanabe, Speakers bureau: YM received a research grant and/or speaker fee from Eli Lilly, Chugai, Pfizer, Bristol-Myers Squibb, and Mitsubishi-Tanabe, Toru Hirano Grant/research support from: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Speakers bureau: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Ryota Hara Speakers bureau: RH received a speaker fee from AbbVie, Kosuke Ebina Grant/research support from: KE has received research grants from Abbie, Asahi-Kasei, Astellas, Chugai, Eisai, Ono Pharmaceutical, and UCB Japan., Employee of: KE is affiliated with the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho., Speakers bureau: KE has received payments for lectures from Abbie, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Sanofi, and UCB Japan., Motomu Hashimoto Grant/research support from: Bristol-Myers Squibb, Eisai, and Eli Lilly and Company., Speakers bureau: Bristol-Myers Squibb and Mitsubishi Tanabe Pharma., Wataru Yamamoto: None declared, Kosaku Murakami Speakers bureau: AbbVie, Eisai, and Mitsubishi Tanabe Pharma., Takuya Kotani: None declared, Kenichiro Hata: None declared, Yonsu Son: None declared, Hideki Amuro: None declared, Akira Onishi Speakers bureau: AO received a speaker fee from Chugai, Ono Pharmaceutical, Eli Lilly, Mitsubishi-Tanabe, Asahi-Kasei, and Takeda, Jinno Sadao: None declared, Masaki Katayama: None declared, Atsushi Kumanogoh Grant/research support from: AK received a research grant and/or speaker fee from Mitsubishi-Tanabe, Chugai, Eisai, Asahi-Kasei, Astellas, Abbvie, Bristol-Myers Squibb, Ono Pharmaceutical, and Pfizer, Speakers bureau: AK received a research grant and/or speaker fee from Mitsubishi-Tanabe, Chugai, Eisai, Asahi-Kasei, Astellas, Abbvie, Bristol-Myers Squibb, Ono Pharmaceutical, and Pfizer

Background:EULAR recommendation announced that biological disease-modifying antirheumatic drugs (bDMARDs) and janus kinase inhibitors (JAKi) are considered as equivalent in the treatment of rheumatoid arthritis (RA). However, we still lack reliable evidence of direct comparison between these agents’ retention, which may reflect both effectiveness and safety.Objectives:The aim of this multi-center (7 university-related hospitals), retrospective study is to clarify retention rates and reasons for discontinuation of 7 bDMARDs and tofacitinib (TOF), one of the JAKi, in both bDMARDs-naïve and bDMARDs-switched cases.Methods:This study assessed 3,897 patients and 4,415 treatment courses of with bDMARDs and TOF from 2001 to 2019 (2,737 bDMARDs-naïve patients and 1,678 bDMARDs-switched patients [59.5% switched to their second agent], female 82.3%, baseline age 57.4 years, disease duration 8.5 years; rheumatoid factor positivity 78.4%; DAS28-ESR 4.3; concomitant prednisolone [PSL] 6.1 mg/day [42.4%] and methotrexate [MTX] 8.5 mg/week [60.9%]). Treatment courses included abatacept (ABT; n=663), adalimumab (ADA; n=536), certolizumab pegol (CZP; n=226), etanercept (ETN; n=856), golimumab (GLM; n=458), infliximab (IFX; n=724), tocilizumab (TCZ; n=851), and TOF (n=101/only bDMARDs-switched cases). Reasons for discontinuation were classified into four categories by each attending physician: 1) lack of effectiveness, 2) toxic adverse events, 3) non-toxic reasons, and 4) remission. Retention rates of each discontinuation reason were estimated at 36 months using the Kaplan-Meier method and adjusted for potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX, starting date and number of switched bDMARDs) using Cox proportional hazards modeling.Results:Adjusted drug retention rates for each discontinuation reason were as follows: lack of effectiveness in the bDMARDs-naïve group (from 70.8% [CZP] to 85.1% [ABT]; P=0.001 between agents) and the bDMARDs-switched group (from 52.8% [CZP] to 78.7% [TCZ]; PConclusion:Remarkable differences were observed in drug retention of 7 bDMARDs and TOF between bDMARDs-naïve and bDMARDs-switched cases.Disclosure of Interests:Kosuke Ebina Grant/research support from: KE has received research grants from Abbie, Asahi-Kasei, Astellas, Chugai, Eisai, Ono Pharmaceutical, and UCB Japan., Employee of: KE is affiliated with the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho., Speakers bureau: KE has received payments for lectures from Abbie, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Sanofi, and UCB Japan., Toru Hirano Grant/research support from: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Speakers bureau: TH received a research grant and/or speaker fee from Astellas, Chugai, Nippon Shinyaku, Abbvie, Eisai, and Ono Pharmaceutical, Yuichi Maeda Grant/research support from: YM received a research grant and/or speaker fee from Eli Lilly, Chugai, Pfizer, Bristol-Myers Squibb, and Mitsubishi-Tanabe, Speakers bureau: YM received a research grant and/or speaker fee from Eli Lilly, Chugai, Pfizer, Bristol-Myers Squibb, and Mitsubishi-Tanabe, Wataru Yamamoto: None declared, Motomu Hashimoto Grant/research support from: Bristol-Myers Squibb, Eisai, and Eli Lilly and Company., Speakers bureau: Bristol-Myers Squibb and Mitsubishi Tanabe Pharma., Koichi Murata Grant/research support from: KMurata belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan)., Employee of: KMurata belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan)., Speakers bureau: KMurak has received speaking fees, and/or consulting fees from Eisai Co. Ltd, Chugai Pharmaceutical Co. Ltd., Pfizer Japan Inc, Bristol-Myers Squibb, Mitsubishi-Tanabe Pharma Corporation, UCB, Daiichi Sankyo Co. Ltd. and Astellas Pharma Inc., Tohru Takeuchi Grant/research support from: TT received a research grant from Chugai, CoverLetter and a speaker fee from Astellas, Chugai, Eisai, Mitsubishi-Tanabe, Abbvie, Bristol-Myers Squibb, Ayumi, Daiichi Sankyo, Eisai, Takeda, and Asahi-Kasei, Employee of: TT is affiliated with a department that is financially supported by six pharmaceutical companies (Mitsubishi-Tanabe, Chugai, Ayumi, Astellas, Eisai, and Takeda), Hideyuki Shiba: None declared, Yonsu Son: None declared, Hideki Amuro: None declared, Akira Onishi Speakers bureau: AO received a speaker fee from Chugai, Ono Pharmaceutical, Eli Lilly, Mitsubishi-Tanabe, Asahi-Kasei, and Takeda, Kengo Akashi: None declared, Ryota Hara Speakers bureau: RH received a speaker fee from AbbVie, Masaki Katayama: None declared, Keiichi Yamamoto: None declared, Atsushi Kumanogoh Grant/research support from: AK received a research grant and/or speaker fee from Mitsubishi-Tanabe, Chugai, Eisai, Asahi-Kasei, Astellas, Abbvie, Bristol-Myers Squibb, Ono Pharmaceutical, and Pfizer, Speakers bureau: AK received a research grant and/or speaker fee from Mitsubishi-Tanabe, Chugai, Eisai, Asahi-Kasei, Astellas, Abbvie, Bristol-Myers Squibb, Ono Pharmaceutical, and Pfizer, Makoto Hirao Speakers bureau: MHirao received a speaker fee from Astellas, Ono Pharmaceutical, Eli Lilly, Mitsubishi-Tanabe, Pfizer, Ayumi, and Takeda

Background A part of rheumatoid arthritis (RA) patients are resistant to clinical remission (CR) irrespective of therapies. In addition to known risk factors, systemic organ complications are assumed to interfere with CR. Objectives To extract the predictive comorbidities of clinical response of disease activities. Methods In Kansai consortium for well-being of rheumatic disease patients (ANSWER) cohort, which was the real world cohort of clinical database of rheumatic diseases, RA patients within 3 years of disease duration were included and followed. Using logistic regression analysis, background factors at the initial visit were extracted in order to predict CR after 1 year (1 year-non CR). Results 651 patients met in the inclusion criteria were under the analysis. Of those, 245 (37.6%) cases were resulted in 1 year-non CR. The average scores of DAS28-CRP at first visit and one year later was 3.51 and 2.02, respectively. Logistic regression analysis revealed that DAS28-CRP at first visit (OR 1.42/unit, 95% CI 1.24–1.63), concomitant use of methotrexate (MTX) or biologic disease modifying rheumatic drugs (bDMARDs) (OR 2.04, 95% CI 1.41–2.96) and body mass index (BMI) (OR 1.07/unit, 95% CI 1.02–1.12) were significant predictive factors of 1 year-non CR, but not in the case with gender, age, disease duration, hypertension, diabetes, dyslipidemia, lung diseases, heart diseases, digestive tissue diseases, history of malignancy nor concomitant autoimmune diseases. Using propensity score matching (1:1) stratified by gender, age, disease duration, concomitant use of MTX or bDMARDs and DAS28-CRP at baseline, the 49 pairs were matched between obese (defined as body mass index (BMI) over than 28) and non-obese patients. In these cohort, mean score of DAS28-CRP after 1 year was significantly higher in obese patients than in non-obese patients (2.63 and 2.18, respectively, see the figure 1). Conclusions In these early arthritis cohort, obese patients tend to remain higher disease activities even considering with gender, age and therapeutic management, although validation studies should be added to confirm these findings. Acknowledgements None. Disclosure of Interest None declared

Background Some experimental models suggested bacterial infection, such as periodontal disease and gut microbiota, might be an inciting and aggravating factor in rheumatoid arthritis (RA)1. Moreover, medications that have an antibacterial effect such as minocycline and sulfasalazine are used as DMARDs. However, the antibacterial effect itself on disease activity are unknown in patients with RA whereas trimethoprim-sulfamethoxazole (TMP-SMX) is often used for Pneumocystis jirovecii pneumonia (PCP) prophylaxis because PCP is a prevalent and potentially life-threatening opportunistic infection among patients with RA, especially in Japan2.3. Objectives To identify the effect of TMP-SMX on disease activity in patients with RA in a multi-center cohort study (ANSWER cohort study). Methods RA patients with a sampling interval of less than 1 year and at least two assessment of disease activity were enrolled. Disease activity was assessed using disease activity score 28-CRP (DAS28-CRP). Linear mixed effect models were used to evaluate the trajectories of disease activity in RA patients. Time from baseline, TMP-SMX administration, and their interaction were included as fixed effects while participant identification number and time from baseline were included as random factors. Age, sex, disease duration, RF, ACPA, HAQ, and DMARDs were included as covariates. Results A total of 49878 samples (mean sampling interval: 49 days) from 3255 patients was included. The median age at baseline was 64.0 years (interquartile range, 53.0 to 71.0 years) with 78.2 % of women (ACPA positivity, 79.2%; RF positivity, 70.8 %). The median DAS28-CRP was 2.83 with 33.8 % of patients taking TMP-SMX at baseline. Patients with taking TMP-SMX had a significantly but minimally better longitudinal trajectory on disease activity than patients without (-0.00012/month, P=0.009). This result was similar even when patients taking sulfasalazine were excluded from analysis. Conclusions TMP-SMX has minimal impact on disease activity, and therefore clinical utility of TMP-SMX for controlling disease besides PCP prophylaxis is limited. These results did not support a theoretical effect of bacterial infection on disease activity in RA, although the effect of the other antibiotics on disease activity should be examined. References: [1] Roszyk E, Puszczewicz M. Role of human microbiome and selected bacterial infections in the pathogenesis of rheumatoid arthritis. Reumatologia 2017;55:242-50. [2] Galli M, Antinori S, Atzeni F, et al. Recommendations for the management of pulmonary fungal infections in patients with rheumatoid arthritis. Clin Exp Rheumatol 2017;35:1018-28. [3] Harigai M, Koike R, Miyasaka N, et al. Pneumocystis pneumonia associated with infliximab in Japan. N Engl J Med 2007;357:1874-6. Acknowledgements: None. Disclosure of Interest: None declared

Background In the treatment of patients with rheumatoid arthritis (RA), glucocorticoids (GCs) with csDMARDs remain an important treatment option given their capacity to increase clinical, structural and functional efficacy. On the other hand, it is reported that GCs usage even at low dosage significantly deteriorated functional capacity in patients with low disease activity state. In these previous study, disease activity and subsequent joint destruction have no small influence on functional disability. Objectives To investigate the effect of the use of glucocorticoids (GCs) in patients with RA who had maintained clinical remission on functional ability. Methods Among 2,649 patients with RA who achieved DAS-ESR Results Characteristics of patients at baseline were as follows (median (IQR), proportion). The age was 61 (48–68) years, female was 70.6%, disease duration was 4.5 (1.7–10.7) years, RF-positive was 64.4%, ACPA-positive was 70%, DAS28-ESR was 2.0 (1.6–2.6), HAQ-DI score was 0.125 (0–0.5). Of the 1,171 patients, 235 (20.1%) patients had been treated with oral GCs when achieving clinical remission. CRP (0.06 (0–0.2) vs 0.03 (0–0.1), p=0.03), MMP-3 (106.1 (73.2–172.8) vs 49.5 (36.5–77.2), p Conclusions The use of GCs in RA patients with sustained remission was the risk factor of progression of HAQ-DI score dose-dependently. Disclosure of Interest None declared

Background Patients with RA have higher risk of developing chronic kidney disease compared to the general population. Although some causes of renal impairment in RA include nephrotoxic medications, amyloidosis, and glomerulonephritis, specific causes are not determined among most patients with RA. While experimental researches showed inflammatory process per se might also contribute to renal dysfunction, the results of previous clinical studies that assessed the effects of disease activity or C-reactive protein on renal function were inconsistent. This inconsistency might be attributable to their cross-sectional design, small sample size, and assessment of association between only baseline characteristics and renal outcomes without consideration for the fact that disease activity and medications had changed over time. Objectives To identify the effects of disease activity on renal function in RA in a multi-center cohort study. Methods RA patients with a sampling interval of less than 150 days were enrolled because wide sampling intervals could not take into consideration changes in disease activity and medications during their follow-up. An estimated glomerular filtration rate (eGFR) was calculated using an equation approved by the Japanese Society of Nephrology and used as an outcome variable. Linear mixed effect models were used to evaluate the renal trajectories of patients. Time from baseline (months), disease activity, and their interaction were included as fixed effects while participant identification number and time from baseline were included as random factors. Age, sex, disease duration, RF, ACPA, NSAIDs, and DMARDs that were known as a cause of renal impairment, such as tacrolimus, iguratimod, and tofacitinib, were included as covariates. Results A total of 25661 samples (mean sampling interval: 2.0 months) from 2104 patients was included. Patients with lower DAS28-CRP had worse renal function at inclusion, but a significantly better longitudinal trajectory on eGFR (0.0079 ml/min/1.73m2 per month, P=0.025). Although all RA patients had naturally progressive renal impairment as they got older, patients who achieved remission or low disease activity had slower renal impairment rate of -0.068 ml/min/1.73m2 per month compared to patients with moderate or high disease activity (-0.084 ml/min/1.73m2 per month; P=0.037). These results were also similar using SDAI or CDAI. Conclusions Lower disease activity results in slower renal impairment. Because the effects of disease activity on renal function are mild, additional measures to protect renal function, such as avoiding nephrotoxic medications and treating cardiovascular risk factors are important. Disclosure of Interest None declared

Background: The aim of this study is to evaluate the retention rates and reasons for discontinuation for seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of elderly patients (65 years of age or older) with rheumatoid arthritis (RA). Methods: This multi-center, retrospective study assessed 1, 098 treatment courses of 661 patients with bDMARDs from 2009 to 2018 (females, 80.7%; baseline age, 71.7 years; disease duration 10.5 years; rheumatoid factor positivity 81.3%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.6; concomitant prednisolone dose 2.8 mg/day (45.6%) and methotrexate dose 4.4 mg/week (56.4%); and 60.2% patients were bio-naïve). Treatment courses included abatacept (ABT; n = 272), tocilizumab (TCZ; n = 234), etanercept (ETN; n = 184), golimumab (GLM; n = 159), infliximab (IFX; n = 101), adalimumab (ADA; n = 97), and certolizumab pegol (CZP; n = 51). Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX, starting date and switched number of bDMARDs) by Cox proportional hazards modeling. Results: A total of 51.2% of treatment courses were stopped, with 25.1% stopping due to lack of effectiveness, 11.8% due to toxic adverse events, 9.7% due to non-toxic reasons, and 4.6% due to remission. Drug retention rates for each discontinuation reason were as follows; lack of effectiveness [from 55.4% (ETN) to 81.6% (ABT); with significant differences between groups (Cox P, Ebina, K., Hashimoto, M., Yamamoto, W. et al. Correction to: Drug tolerability and reasons for discontinuation of seven biologics in 4466 treatment courses of rheumatoid arthritis -the ANSWER cohort study-. Arthritis Res Ther 21, 114 (2019).

Objective.Biologic treatments including the humanized anti-interleukin 6 (anti-IL-6) receptor antibody tocilizumab (TCZ) provide therapeutic options for patients with rheumatoid arthritis (RA). We investigated useful biomarkers to predict the responsiveness to TCZ by measurement of serum proinflammatory cytokine concentrations.Methods.Serum samples were collected from 61 patients with RA before biologic treatment and at 4 weeks after initial administration of either TCZ (n = 32) or infliximab (IFX; n = 29) and from 13 healthy serum donor controls. Disease Activity Score of 28 joints (DAS28) was determined at baseline and after treatment.Results.Although IL-1β, IL-2, IL-6, IL-17A, IL-17F, interferon-α, and tumor necrosis factor-α (TNF-α) were all increased in sera from patients with RA compared with controls, only the IL-6 level was significantly correlated with DAS28 before treatment. The IL-6 level before treatment was positively correlated with DAS28 after TCZ treatment, and was significantly lower in TCZ-responsive patients (as judged by a post-treatment DAS28 < 3.2) than in TCZ-resistant patients (post-treatment DAS28 ≥ 3.2). DAS28 after TCZ was significantly lower than after administration of IFX in patients with low pretreatment IL-6 (< 51.5 pg/ml, the mean baseline value of IL-6 in all RA patients), but not in those with high pretreatment IL-6. These results indicate that low serum IL-6 is associated with a favorable response to TCZ.Conclusion.Although both TNF-α and IL-6 are major targets of therapeutic intervention in RA, baseline serum IL-6 but not baseline TNF-α level is a potential biomarker reflecting disease activity. Measurement of serum IL-6 in RA before treatment may be useful to estimate residual disease activity after TCZ treatment and to predict responsiveness to TCZ treatment.

Background Clinical remission can be maintained after the discontinuation of biological disease-modifying antirheumatic drugs (bDMARDs) in some patients with rheumatoid arthritis (RA) (bDMARD-free remission (BFR)). It is unknown which bDMARD is advantageous for achieving BFR or under which conditions BFR can be considered. This study aimed to determine the factors associated with BFR achievement in clinical practice. Methods Patients with RA were enrolled from a Japanese multicenter observational registry. Patients with RA who achieved clinical remission (Disease Activity Score 28—C-reactive protein 6 months), Boolean remission, no glucocorticoid use at the time of bDMARD discontinuation, and use of TNFi(mAb) or CTLA4-Ig remained as independent factors associated with BFR. Conclusions BFR can be achieved in some patients with RA after bDMARD discontinuation in clinical practice. Use of TNFi(mAb) or CTLA4-Ig, sustained remission, Boolean remission, and no glucocorticoid use at the time of bDMARD discontinuation are advantageous for achieving BFR. Electronic supplementary material The online version of this article (10.1186/s13075-018-1673-1) contains supplementary material, which is available to authorized users.

Although Bacillus Calmette-Guérin (BCG) has historically emerged as a potent adjuvant in cancer immunization through dendritic cell (DC) activation, the efficacy of its antitumor effect has been limited. Therefore, the strategy of adjuvant therapy using BCG needs to be improved by adding enhancers. Here we found that thymic stromal lymphopoietin (TSLP) acts as an enhancer for the BCG-mediated antitumor effect. While BCG-stimulated DCs induced CD8(+) T cell production of IFN-gamma without strong cell expansion, TSLP-stimulated DCs induced robust CD8(+) T cell expansion without high quantities of IFN-gamma production. Notably, DCs stimulated with both BCG and TSLP induced robust expansion of CD8(+) T cells that produced a large amount of IFN-gamma with a potent cytolytic activity related to granzyme B expression. Our data suggest that TSLP is a good adjuvant to enhance the BCG-mediated cytotoxic T cell effect through DC activation, and provide a functional basis for a novel strategy for antitumor immune-based therapy.

The purpose of this study was to evaluate the retention and discontinuation reasons of seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). 1, 037 treatment courses with bDMARDs from 2009 to 2016 [female, 81.8%; baseline age, 59.6 y; disease duration 7.8 y; rheumatoid factor positivity 81.5%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR), 4.4; concomitant prednisolone 43.5% and methotrexate 68.6%; Bio-naïve, 57.1%; abatacept (ABT), 21.3%; tocilizumab (TCZ), 20.7%; golimumab (GLM), 16.9%; etanercept (ETN), 13.6%; adalimumab (ADA), 11.1%; infliximab (IFX), 8.5%; certolizumab pegol (CZP), 7.9%] were included in this multi-center, retrospective study. Drug retention and discontinuation reasons at 36 months were estimated using the Kaplan-Meier method and adjusted by potent confounders using Cox proportional hazards modeling. As a result, 455 treatment courses (43.9%) were stopped, with 217 (20.9%) stopping due to inefficacy, 113 (10.9%) due to non-toxic reasons, 86 (8.3%) due to toxic adverse events, and 39 (3.8%) due to remission. Drug retention rates in the adjusted model were as follows: total retention (ABT, 60.7%; ADA, 32.7%; CZP, 43.3%; ETN, 51.9%; GLM, 45.4%; IFX, 31.1%; and TCZ, 59.2%; P < 0.001); inefficacy (ABT, 81.4%; ADA, 65.7%; CZP, 60.7%; ETN, 71.3%; GLM, 68.5%; IFX, 65.0%; and TCZ, 81.4%; P = 0.015), toxic adverse events (ABT, 89.8%; ADA, 80.5%; CZP, 83.9%; ETN, 89.2%; GLM, 85.5%; IFX, 75.6%; and TCZ, 77.2%; P = 0.50), and remission (ABT, 95.5%; ADA, 88.1%; CZP, 91.1%; ETN, 97.5%; GLM, 94.7%; IFX, 86.4%; and TCZ, 98.4%; P < 0.001). In the treatment of RA, ABT and TCZ showed higher overall retention, and TCZ showed lower inefficacy compared to IFX, while IFX showed higher discontinuation due to remission compared to ABT, ETN, GLM, and TCZ in adjusted modeling.

Atopic dermatitis is a major allergic disease that develops through dysregulation of Th2-mediated inflammation. Although dendritic cells (DCs) have been thought to play a critical role in the upstream phase of the allergic cascade, conventional drugs such as steroids and chemical mediator antagonists target the effector cells or factors in allergic inflammation. Recently, it has been demonstrated that interaction between thymic stromal lymphopoietin (TSLP) and human DCs plays an essential role in evoking inflammatory Th2 responses in allergy through OX40 ligand expression on DCs. In this study, we provide evidence that R848, an imidazoquinoline compound, which is a TLR ligand and a strong Th1 response-inducing reagent, is a potent adjuvant for the alteration of the Th2-inducing potency of human DCs activated by TSLP (TSLP-DCs). R848 inhibited the inflammatory Th2-inducing capacity of TSLP-DCs and redirected them to possessing an IL-10 and IFN-γ-producing regulatory Th1-inducing capacity. This functional alteration depended on both repression of OX40 ligand expression and induction of IL-12 production from DCs by the addition of R848. Additionally, R848 had the ability to inhibit the TSLP-mediated expansion and maintenance of the Th2 memory response. These findings suggest that imidazoquinoline may be a useful in the treatment of allergic diseases that are triggered by TSLP.

Allergic diseases such as atopic dermatitis and asthma develop as a consequence of dysregulated T(h)2 responses. Recently, it has been demonstrated that interaction between dendritic cells (DCs) and thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine, is essential for evoking T(h)2 responses in allergy. In this study, we investigated whether Mycobacterium bovis Bacillus Calmette-Guérin (BCG), a strong T(h)1 response-inducing adjuvant, can alter the function of DCs activated by TSLP (TSLP-DCs). We demonstrated that BCG redirects TSLP-DCs away from inducing inflammatory T(h)2 cells that produce IL-4, IL-5, IL-13 and tumor necrosis factor (TNF)-alpha and toward regulatory T(h)1 cells that produce IFN-gamma and IL-10. We also demonstrated that this functional alteration of TSLP-DCs by BCG depended on both production of IL-12 from DCs and down-regulation of OX40 ligand, a member of the TNF family, on DCs. These findings suggest that BCG might be a useful adjuvant for the treatment of allergic diseases that are triggered by TSLP.

Adult-onset Still's disease (AOSD) is a rheumatoid disorder characterized by high fever, polyarthritis, leukocytosis, hyperferritinaemia, and mild liver involvement. We describe the case of a patient with AOSD with severe liver dysfunction. His serum levels of interleukin-10 and 18 showed a similar trend to his disease activity. Drug lymphocyte stimulation tests were positive for three drugs in the patient. Hypercytokinaemia was controlled by plasma exchange therapy.

Pneumomediastinum is a rare complication of dermatomyositis (DM) and Polymiositis (PM). We report here three cases of PM/DM who developed pneumomediastinum. First case was 61 years old woman with amyopathic dermatomyositis (aDM). Her aDM was complicated with skin ulceration due to vasculopathy, but complicated interstitial pneumonia was not severe. She developed subcutaneous emphysema and pneumomediastinum. Second case was 57 years old woman with DM, who had intractable skin phenomena and mild interstitial pneumonia. The patient became subcutaneous emphysema and pneumomediastinum following severe vasculopathy of skin. The last case was 63 years old man with PM. His PM was complicated with interstitial pneumonia. He had intractable respiratory symptom. Ten years later, he became subcutaneous emphysema and pneumomediastinum following pneumothorax. First and second cases suggest that their pneumomediastinum were due to vasculopathy. On the other hand, pneumomediastinum of the last patient seemed to be associated with interstitial pneumonia and steroid.