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Background: We examined the real-world drug retention rate and safety data of Janus kinase inhibitors (JAKis) in elderly patients with rheumatoid arthritis (RA). Methods: This study enrolled 133 RA patients (≥65 years) with sufficient clinical data who were initiated with JAKis during the study period. These patients were divided into two groups: the very elderly group (≥ 75 years) and the elderly group (65 ≤ years < 75). The drug retention rates of JAKis were compared using Kaplan–Meier curves. Results: The discontinuation rates of JAKis were as follows: lack of effectiveness 27 (20.3%), adverse events (AEs) 29 (21.8%), and remission 2 (1.5%). There was no significant difference in the overall drug retention rate between the very elderly group (≥75 years) and the elderly group. Furthermore, the overall drug retention rates of JAKis were not affected by gender, methotrexate use, and anti-citrullinated protein/peptide antibody (ACPA) status. The discontinuation rates of JAKis due to AEs were comparable both in the very elderly group (≥75 years) and the elderly group (65 ≤ years < 75). Whereas chronic lung disease and hypoalbuminemia were independently associated with discontinuation rates due to AEs, the overall drug retention rates were significantly lower in patients treated with the approved dose of JAKis than in those treated with a reduced or tapered dose. Conclusions: Our results suggest that the overall drug retention rate of JAKis in very elderly patients (≥75 years) was comparable with that in elderly patients (65 ≤ years < 75). The discontinuation rates of JAKis due to AEs were also comparable both in very elderly group patients and elderly patients.

Background: In this retrospective cohort study, we compared the retention rates and effectiveness of biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs: Janus kinase inhibitors) in elderly patients with rheumatoid arthritis (RA).Methods: One hundred thirty four elderly RA patients (>65 years) who were initiated with bDMARDs (n = 80) or Janus kinase inhibitors (JAKi) (n = 54) between 2016 and 2020 in our institute were enrolled in this analysis. Follow-up was conducted at 4-week intervals from the start of bDMARDs or JAKi. We compared the drug relation and clinical response at 24 week between elderly RA patients treated with bDMARDs and JAKi. Results: In the demographic data, longer disease duration, higher previous bDMARDs use and lower glucocorticoid use were observed in JAKi group. Otherwise there was no significant difference in the other variables between the bDMARDs and JAKi groups. In the matched analysis, there was no significant difference in drug retention rates between bDMARDs and JAKi groups. There was no significant difference in the incidence of drug discontinuation due to lack of effectiveness between the two groups. Also, there was no significant difference in the proportion of patients achieving good/moderate EULAR response at 24 week between these two groups. Conclusions: In elderly RA patients initiated with bDMARDs or JAKi, drug retention rates of these targeted therapies did not differ significantly between these two groups. These findings suggest that elderly RA patients can achieve similar clinical improvement after initiating bDMARDs or JAKi.

Ferredoxin-NADP+ reductase (FNR) in plants receives electrons from ferredoxin (Fd) and converts NADP+ to NADPH at the end of the photosynthetic electron transfer chain. We previously showed that the interaction between FNR and Fd was weakened by the allosteric binding of NADP(H) on FNR, which was considered as a part of negative cooperativity. In this study, we investigated the molecular mechanism of this phenomenon using maize FNR and Fd, as the three-dimensional structure of this Fd:FNR complex is available. NMR chemical shift perturbation analysis identified a site (Asp60) on Fd molecule which was selectively affected by NADP(H) binding on FNR. Asp60 of Fd forms a salt bridge with Lys33 of FNR in the complex. Site-specific mutants of FdD60 and FNRK33 suppressed the negative cooperativity (downregulation of the interaction between FNR and Fd by NADPH), indicating that a salt bridge between FdD60 and FNRK33 is involved in this negative cooperativity.

The genome contains large functional units ranging in size from hundreds of kilobases to megabases, such as gene clusters and topologically associating domains. To analyse these large functional units, the technique of deleting the entire functional unit is effective. However, deletion of such large regions is less efficient than conventional genome editing, especially in cultured cells, and a method that can ensure success is anticipated. Here, we compared methods to delete the 2.5-Mb Krüppel-associated box zinc finger protein (KRAB-ZFP) gene cluster in mouse embryonic stem cells using CRISPR-Cas9. Three methods were used: first, deletion by non-homologous end joining (NHEJ); second, homology-directed repair (HDR) using a single-stranded oligodeoxynucleotide (ssODN); and third, HDR employing targeting vectors with a selectable marker and 1-kb homology arms. NHEJ-mediated deletion was achieved in 9% of the transfected cells. Inversion was also detected at similar efficiency. The deletion frequency of NHEJ and HDR was found to be comparable when the ssODN was transfected. Deletion frequency was highest when targeting vectors were introduced, with deletions occurring in 31–63% of the drug-resistant clones. Biallelic deletion was observed when targeting vectors were used. This study will serve as a benchmark for the introduction of large deletions into the genome.

In chloroplast stroma, dynamic pH change occurs in response to fluctuating light conditions. We investigated the pH-dependent electron transfer activity between ferredoxin-NADP+ reductase (FNR) and ferredoxin (Fd) isoproteins from maize leaves. By increasing pH (from 5.5 to 8.5), the electron transfer activity from FNR to photosynthetic-type Fd (Fd1) significantly increased while the activity to nonphotosynthetic type Fd (Fd3) decreased, which was mainly due to their differences in the pH dependency of Km for Fd. Mutation of His78 of Fd1 to Val, corresponding amino acid residue in Fd3, lost the pH dependency, indicating a regulatory role of the His78 in the interaction with FNR. We previously showed that the interaction between FNR and Fd was weakened by the allosteric binding of NADP(H) on FNR. His78Val Fd1 mutant largely suppressed this negative cooperativity. These results indicate the involvement of Fd1 His78 in pH dependency and negative cooperativity in the interaction with FNR.

Ferredoxin-NADP+ reductase (FNR) in plants receives electrons from ferredoxin (Fd) at the end of the photosynthetic electron transfer chain and converts NADP+ to NADPH. The interaction between Fd and FNR in plants was previously shown to be attenuated by NADP(H). Here, we investigated the molecular mechanism of this phenomenon using maize FNR and Fd, as the three-dimensional structure of this complex is available. NADPH, NADP+ , and 2'5'-ADP differentially affected the interaction, as revealed through kinetic and physical binding analyses. Site-directed mutations of FNR which change the affinity for NADPH altered the affinity for Fd in the opposite direction to that for NADPH. We propose that the binding of NADP(H) causes a conformational change of FNR which is transferred to the Fd-binding region through different domains of FNR, resulting in allosteric changes in the affinity for Fd.

Objectives: To identify predictive factors for remission by tocilizumab monotherapy in rheumatoid arthritis (RA) patients.Methods: This is a post hoc analysis of the SURPRISE study, a 2-year random...

ObjectiveTo evaluate the sustained remission and low disease activity after discontinuation of tocilizumab in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate.MethodsThe SURPRISE study was a 2-year, open-label randomised controlled study. Among patients who had been randomised to additional tocilizumab (ADD-ON) or switch to tocilizumab (SWITCH) in the first year, those who achieved remission based on the disease activity score for 28 joints (DAS28-ESRResultsA total of 105 patients who achieved remission at week 52 discontinued tocilizumab; 51 in ADD-ON continued methotrexate and 54 in SWITCH received no disease-modifying antirheumatic drugs. Sustained DAS28 low disease-activity rates were significantly higher in ADD-ON than in SWITCH (55%vs27%, p=0.005). Sustained remission rates at week 104 were 24% for ADD-ON and 14% for SWITCH (p=0.29). Radiological progression was comparable between both groups (mTSS; 0.37vs0.64, p=0.36). The restart of tocilizumab induced remission in all except two patients after 36 weeks, irrespective of concomitant methotrexate.ConclusionSustained low disease activity after tocilizumab discontinuation could be maintained with continued methotrexate in more than half of the patients. Retreatment with tocilizumab led to remission in more than 90% of patients.Trial registration numberNCT01120366; Results.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive clinically amyopathic dermatomyositis (CADM) is frequently associated with rapidly progressive interstitial lung disease (RP-ILD) resulting in high mortality. Here we report a 51-year-old Japanese woman with anti-MDA5 antibody-positive hypomyopathic dermatomyositis (DM) who developed RP-ILD. She developed respiratory failure and pneumomediastinum, however her RP-ILD responded favorably to the combined immunosuppressive treatments consisting of steroids, intravenous cyclophosphamide and tacrolimus. She was complicated with severe infections, which were successfully managed by combined modality therapy including artificial ventilation and antibiotics in addition to immunosuppressive treatments in parallel to the decline of anti-MDA5 antibody titer (>150 Index to 75 Index). She was discharged after 6 months of treatment without any respiratory sequelae. Hypomyopathic DM patients with high titers of anti-MDA5 antibody should be treated with aggressive immunosuppressive therapies and closely monitored to prevent various infections.

Background The prophylaxis for hepatitis B virus (HBV) reactivation assumes that hepatic injury after reactivation is often rapidly progressive and can evoke fulminant hepatitis. The incidence and prognosis of reactivation in patients with rheumatoid arthritis (RA) may be different from those receiving organ transplantation and cancer chemotherapy. This study aimed to investigate the incidence, risk factors, and clinical course of HBV reactivation and develop a scoring system for risk stratification in RA patients with resolved infection. Methods HBV DNA was measured using real-time polymerase chain reaction, and patient data were collected for 4 years in RA patients with resolved HBV infection who were treated with steroids or synthetic or biologic immunosuppressive drugs. Results Among 1127 patients, HBV DNA was detected in 57 patients (1.65/100 person-years); none of the reactivated patients exhibited worsening of hepatic function. Multivariate logistical analysis revealed that age > 70 years and HB core antibody (HBcAb) positivity alone were independent risk factors for HBV reactivation. HBV DNA ≥ 2.1 log copies/mL was observed in 15 patients (0.43/100 person-years); seven patients were treated with nucleic acid analogs (NAAs), whereas the remaining eight were observed without treatment. Among reactivated cases, 15 cases changed to HBV DNA-negative status spontaneously, whereas 24 cases remained HBV DNA positive 70 years) + 2 × (HBcAb positivity alone) + 1 × (treatment other than methotrexate monotherapy). This revealed that patients with the highest score had an odds ratio of 13.01 for HBV reactivation, compared to those with the lowest score. Conclusions Rapid progression and poor outcomes after HBV reactivation were not frequent in RA patients with resolved infection. Our new risk scoring system might be useful for screening and optimization of prophylactic treatment by distinguishing patients with significantly lower reactivation risk.

Background: Interleukin (IL)-6 pathway inhibitors are suggested by European League Against Rheumatism recommendations to have some advantages in rheumatoid arthritis (RA) patients who are not suitable to use methotrexate as comedication compared with other biological disease-modifying antirheumatic drugs. However, it remains to be elucidated what predicts remission achievement by IL-6 pathway inhibitor monotherapy. Objectives: To identify predictive factors for clinical and structural remission by tocilizumab without methotrexate in patients with RA. Methods: This is a post hoc analysis of the SURPRISE study, a 2-year randomized, controlled study comparing the efficacy of tocilizumab with (ADD-ON) and without methotrexate (SWITCH) in active RA patients despite methotrexate therapy. The primary endpoint was the DAS28-ESR remission ( Results: In SWITCH (n = 96), CRP, SAA, RF and DAS28 at baseline showed predictive value for DAS28 remission at week 24 in univariate analysis. Multivariate analysis confirmed SAA, RF and DAS28 at baseline, but not CRP, as predictive factors, with SAA having the highest value (OR [95%CI] by decrease of 5.0 μg/mL = 1.011 [1.002-1.020], p = 0.01, ROC-AUC = 0.731). SAA of Conclusion: SAA levels at baseline can predict the necessity of concomitant methotrexate in tocilizumab initiation in patients with RA. Patients with low levels of SAA at baseline may benefit similarly from tocilizumab therapy with and without methotrexate in terms of achieving clinical and structural remission. Reference: [1] Kaneko Y, et al. Ann Rheum Dis. 2016 Nov;75(11):1917-1923. Kaneko Y, et al. Ann Rheum Dis. 2018 Sep;77(9):1268-1275. Disclosure of Interests: : Masaru Kato Grant/research support from: GSK, Actelion, Speakers bureau: GSK, Actelion, Bayer, Nippon Shinyaku, Eli Lilly, Chugai, Pfizer, Ayumi, Eisai, Asahi Kasei, Yuko Kaneko Grant/research support from: Abbvie, Eisai, Speakers bureau: AbbVie, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Jansen, Kissei, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi, UCB, Yoshiya Tanaka Grant/research support from: Abbvie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, Taisho-Toyama, Takeda, Speakers bureau: Abbvie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Eisai, Glaxo-Smithkline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer Japan Inc, Sanofi, Takeda, UCB, YL Biologics, Masayuki Inoo: None declared, Hitomi Kobayashi-Haraoka: None declared, Koichi Amano Grant/research support from: Asahi Kasei Pharma, Chugai Pharmaceutical Co. Ltd., Speakers bureau: AbbVie GK, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma, Pfizer Japan Inc., Masayuki Miyata: None declared, Yohko Murakawa Grant/research support from: Asahi Kasei Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Teijin Pharma Ltd., Eisai Co., Ltd., Nippon Kayaku Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Paid instructor for: Kissei Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K. Eisai Co., Ltd., Speakers bureau: Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., UCB Japan Co. Ltd., Chugai Pharmaceutical Co., Ltd., AbbVie GK, Daiichi Sankyo Co., Ltd., AYUMI Pharmaceutical Corporation, Janssen Pharmaceutical K.K., Takeda Pharmaceutical Company Limited, Sanofi K.K. Teijin Pharma Ltd., Eli Lilly Japan K.K., Eisai Co., Ltd., Hidekata Yasuoka: None declared, Shintaro Hirata Grant/research support from: Eli Lilly, UCB, Consultant for: Bristol-Myers Squibb, Jansen, UCB, Paid instructor for: AbbVie, Eisai, Tanabe-Mitsubishi, Speakers bureau: AbbVie, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Jansen, Kissei, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi, UCB, Hayato Nagasawa: None declared, Eiichi Tanaka Speakers bureau: Abbvie, Asahi Kasei pharma co., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Co., Eisai Pharmaceutical, Janssen Pharmaceutical K.K., Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical Co., and UCB Pharma., Nobuyuki Miyasaka: None declared, Hisashi Yamanaka Grant/research support from: AbbVie, Eisai, Bristol-Meyers, Novartis, Behringer, Astellas, Kaken, Nippon-Shinyaku, Pfizer, UCB, Ayumi, Ono, Daiichi-Sankyo, Taisyo-Toyama, Takeda, Tanabe-Mitsubishi, Chugai, Teijin Pharma, Torii, YLbio, Speakers bureau: Bristol-Meyers, Astellas, Pfizer, Daiichi-Sankyo, Takeda, Tanabe-Mitsubishi, Chugai, Teijin Pharma, YLbio, Kazuhiko Yamamoto Grant/research support from: Astellas, BMS, Daiichi-Sankyo, Mitsubishi Tanabe, Pfizer, Ayumi, Takeda, Chugai, Eisai, Taisho Toyama, UCB, Janssen, Eli Lilly, and NIPPON KAYAKU., Speakers bureau: Astellas, BMS, Daiichi-Sankyo, Mitsubishi Tanabe, Pfizer, Ayumi, Takeda, Chugai, Eisai, Taisho Toyama, UCB, Janssen, Eli Lilly, and NIPPON KAYAKU., Isao Yokota Speakers bureau: Chugai Pharma, Tatsuya Atsumi Grant/research support from: Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Otsuka Pharmaceutical Co., Ltd. and Pfizer Inc.. Alexion Inc., Bayer Yakuhin, Ltd,Otsuka Pharmaceutical Co., Ltd. Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eisai Co., Ltd., Bristol-Myers Squibb Co., Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma Co., Asahi Kasei Pharma Co., Consultant for: ONO PHARMACEUTICAL CO., LTD Sanofi K.K. Daiichi Sankyo Co., Ltd. Pfizer Inc., Speakers bureau: Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Pfizer Inc.,Daiichi Sankyo Co. Ltd., Bristol-Myers Squibb Co., Eli Lilly Japan K.K., Tsutomu Takeuchi Grant/research support from: Astellas Pharma Inc, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., AbbVie GK, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation, Nipponkayaku Co. Ltd., Novartis Pharma K.K., Grant/research support from: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Grant/research support from: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Abbivie GK, Nipponkayaku Co.Ltd, Janssen Pharmaceutical K.K., Astellas Pharma Inc., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., GlaxoSmithKline K.K., UCB Japan Co. Ltd., Consultant for: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Asahi Kasei Medical K.K., AbbVie GK, Daiichi Sankyo Co., Ltd., Bristol Myers Squibb, and Nipponkayaku Co. Ltd., Speakers bureau: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Speakers bureau: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Astellas Pharma Inc, Diaichi Sankyo Co. Ltd., Eisai Co. Ltd., Sanofi K.K., Teijin Pharma Ltd., Takeda Pharmaceutical Co. Ltd., Novartis Pharma K.K.

A 66-year-old man was referred to our hospital with an increasing subepithelial lesion in the gastric antrum. Using esophagogastroduodenoscopy, a tumor with a steep, 20-mm-high rise protruding in the lumen was observed. The mucosal surface of the tumor was reddish, with ulcers forming at the base. Moreover, the tumor was mobile and soft. A biopsy specimen was taken from the ulcer, but tumor tissue was not collected from the submucosa. Endoscopic ultrasonography (EUS) showed a high echoic mass in the submucosa. However, because the mucosal surface of the ulceration was red, the mesenchymal tumor with internal bleeding was inferred to be lipoma. Additionally, because the tumor was small, flexible, and soft, collecting tumor tissue under EUS-guided fine-needle aspiration was inferred as difficult. We were unable to make a final diagnosis because the lesion showed a small tumor with atypical macroscopic morphology. Therefore, endoscopic submucosa dissection (ESD) was chosen for the diagnostic treatment. Sodium hyaluronate sufficient for separation from the muscular layer was injected into the submucosa. Then submucosal dissection was performed just above the muscle layer. Results demonstrate the possibility of removing the tumor reliably without perforation. Pathological evaluation of the ESD specimen indicated a diagnosis of gastric lipoma.

ObjectiveTo compare the efficacy and safety between tocilizumab added to methotrexate and tocilizumab switched from methotrexate in patients with active rheumatoid arthritis (RA).MethodsThis is a 2-year randomised, controlled study. RA patients with moderate or high disease activity despite methotrexate were randomly assigned either to tocilizumab added to methotrexate (add-on) or tocilizumab switched from methotrexate (switch). The primary endpoint was the DAS28 remission rate at week 24. Secondary objectives included other clinical efficacy indices, radiological outcomes assessed with the van der Heijde-modified total Sharp scoring system (mTSS), and safety.ResultsOf 223 randomised patients, 83% completed 52 weeks. DAS28 remission rates at week 24 were 70% for add-on and 55% for switch (p=0.02), but they became comparable at week 52 (72% vs 70%, p=0.86). Structural remission rates (mTSS≤0.5) at week 52 were not different (66% vs 64%, p=0.92). However, clinically relevant radiographic progression rates (CRRP; mTSS≥3) tended to be higher with the switch than with the add-on (15% vs 7%, p=0.07). Radiographic progression in the CRRP patients was larger with the switch than with the add-on (9.0/year vs 5.0/year, p=0.04). The difference in the mean C-reactive protein of the CRRP patients was significant for the first 24 weeks (1.56 vs 0.49, p=0.001) but not for the following 28 weeks (0.10 vs 0.04, p=0.1). Overall safety was preferable in the switch group.ConclusionsIn RA patients with inadequate response to methotrexate, tocilizumab added to methotrexate more rapidly suppressed inflammation than tocilizumab switched from methotrexate, leading to superior clinical efficacy and prevention of joint destruction.Trial registration numberNCT01120366.

To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA).In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients.When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (ΔmTSS/year ≤ 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (ΔmTSS ≤ 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes.TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

Introduction Triamcinolone acetonide (TA), a steroid, is often used clinically to prevent dysfunctions associated with fibrosis. The objective of this study was to examine whether TA can be suspended in a gelatin sheet for tissue engineering using a mouse skin wound model. Methods TA was suspended in biodegradable gelatin and freeze-dried in a sheet form. The sheet was analyzed for homogeneity and controlled release of TA by high-performance liquid chromatography. We made two skin wounds on the dorsal side of mice. Gelatin sheets with TA (TA sheet) and without TA (control sheet) were attached to each skin wound. To determine the efficacy of the prepared TA sheet on the skin wounds, TA-sheet versus TA-injection experiments were conducted. Hematoxylin and eosin staining was performed to assess the grade of epithelialization and alpha smooth muscle actin (α-SMA) immunohistochemical staining was conducted to evaluate myofibroblast infiltration. Results In the TA-release test in vitro, 7.7 ± 2.3% of TA was released from the sheet by 24 h. After replacing the initial phosphate-buffered saline (PBS) with collagenase PBS, the amount of released TA increased over time. The wound area/original skin wound area after 15 days with the TA sheet was significantly larger than that with the control sheet (26.9 ± 5.5% vs 10.7 ± 2.6%, p = 0.023). The α-SMA positive area/whole area with the TA sheet was significantly lower than that with the control sheet (4.65 ± 0.66% vs 7.24 ± 0.7%, p = 0.023). Furthermore, the α-SMA positive area/whole area with the TA sheet was significantly lower than that with TA injection (5.32 ± 0.45% vs 7.93 ± 0.75%, p = 0.013). Conclusions We developed a TA sheet and confirmed both the homogeneity of the suspended TA and controlled-release of the TA in the presence of collagenase in vitro. The TA sheet caused less myofibroblast infiltration into the tissue than the control sheet or TA injection did., Highlights • We produced a gelatin sheet containing triamcinolone acetonide (TA). • TA homogeneity and controlled-release with collagenase in vitro was confirmed. • TA sheet attached to the injured skin of a mouse reduced myofibroblast infiltration. • Clinical situations with aberrant local fibrosis could be treated with the TA sheet.

Objectives: To validate the usefulness of a hepatic fibrosis scoring system fibrosis-4 (FIB-4) index to diagnose liver diseases in rheumatoid arthritis (RA) patients treated with methotrexate (MTX).Methods: The FIB-4 index (age(years) × AST(U/L)/platelet (PLT) (109/L) × √ALT(U/L)), proposed as a predictor for liver fibrosis in HIV/HCV coinfection, was evaluated in this study. RA patients on MTX treatment were screened by FIB-4 index values to detect fibrotic change in the liver. Liver biopsy specimens were examined histologically in patients with high values.Results: Thirteen of 14 patients showed histology closely resembling non-alcoholic steatohepatitis. In three of them, two biopsies were performed: 1st, during MTX treatment; and 2nd, after discontinuation of MTX. All of them showed improvement in histology along with decreased FIB-4 values. Age, AST/√ALT, and 1/PLT, as well as creatinine levels and cumulative MTX doses were significantly higher in the high FIB-4 group compared with the low FIB-4 group. In the high FIB-4 group, 1/PLT and AST/√ALT were significantly correlated with FIB-4 values, but age was not.Conclusions: The FIB-4 index is simple to calculate and a valuable marker to diagnose liver disease in RA patients treated with long-term MTX administration.

Hepatitis B virus (HBV) reactivation has been increasingly recognized in patients receiving chemotherapy and immunosuppressive therapy; however, the prevalence of HBV infection and rate of HBV screening in patients with rheumatic diseases remains unclear. In this study, we aimed to assess the prevalence of HBV infection and fulminant HBV hepatitis in patients with rheumatic diseases. We also investigated the rate of HBV screening before immunosuppressive therapy in patients with rheumatic diseases. A retrospective questionnaire survey was conducted in the North-east area (Tohoku) of Japan. Questionnaires, comprising 6 questions, were sent to 318 rheumatologists in May 2010, and responses were gathered until June 2011. In total, 71 rheumatologists (22.3%) responded to the survey. We enrolled 7,650 patients with rheumatoid arthritis (RA) and 1,031 patients with systemic lupus erythematosus (SLE). When limited to institutes at which almost all (≥ 90%) patients were tested for HBV serology, 1.1% (40/3,580) patients with RA and 0.3% (3/1,128) patients with SLE were positive for hepatitis B surface antigen (HBsAg), and 25.2% (177/703) patients with RA and 13.7% (34/248) patients with SLE were positive for hepatitis B core antibody (HBcAb). About one-third of rheumatologists did not check HBsAg and more than half did not check hepatitis B surface antibody (HBsAb) or HBcAb at all before therapy. Fulminant HBV hepatitis was observed in 1 RA patient who was current HBV carrier. In conclusion, the prevalence of HBV infection is high in patients with RA and SLE. HBV screening before immunosuppressive therapy should be strictly performed.

BackgroundAlthough the reactivation of hepatitis B virus (HBV) is recognised as a serious complication in patients with rheumatic disease (RD) receiving immunosuppressive drugs (ISDs), the incidence and risk factors for reactivation remain controversial.ObjectivesTo investigate the incidence and risk factors for HBV reactivation in patients with RD.MethodsWe performed a multicentre, observational, prospective study over 2 years in patients with resolved HBV infection. Patients with RD treated with a dose of ≥5 mg/day prednisolone and/or synthetic or biological ISDs with negative HB virus surface antigen and positive anti-HB virus surface antibody (HBsAb) and/or anti-HB virus core antibody (HBcAb) were enrolled. Quantitative HBV DNA results and related data were regularly recorded.ResultsAmong 1042 patients, including 959 with rheumatoid arthritis, HBV DNA was detected in 35 (1.93/100 person-years), with >2.1 log copies/mL observed in 10 patients (0.55/100 person-years). None of the reactivated patients, including seven treated with a nucleic acid analogue, showed overt hepatitis. Low HBsAb titres and advanced age seemed to be risk factors for HBV reactivation; however, reactivation was observed in three patients with positive HBsAb and negative HBcAb test results. The risk of reactivation was lower with methotrexate but higher with prednisolone among the different types of ISDs. The intervals from the start of ISD to reactivation were relatively long (3–182 months; median, 66 months).ConclusionsThe incidence of HBV reactivation with ISD use was 1.93/100 person-years in patients with RD with resolved HBV infection. No overt hepatitis was observed in the reactivated patients.

A 63-year-old woman was referred to Fukushima Red Cross Hospital with an enlargement of the left submandibular gland and subcutaneous bleeding in the chest and legs. A diffuse enlargement of the pancreas was also detected by abdominal computed tomography, and laboratory data showed severe thrombocytopenia. She was diagnosed with IgG4-related disease (IgG4-RD) complicated with autoimmune thrombocytopenia and was treated with methylprednisolone, after which the number of platelets favorably increased. Further investigation for liver dysfunction revealed underlying primary biliary cirrhosis (PBC). We herein report a rare case of IgG4-RD overlapping PBC complicated with autoimmune thrombocytopenia.

An 84-year-old-man was admitted to the Department of Neurosurgery for a sudden episode of fainting. Brain computed tomography and magnetic resonance imaging demonstrated no fresh lesions. Anorexia, fever and elevation of C-reactive protein and creatine phosphokinase were observed, and the patient was transferred to the Department of Internal Medicine for further examination and treatment. High-dose steroids and antibiotics were administered, and his fever subsided. However, massive hemoptysis suddenly developed and the patient died. A thoracic aortic aneurysm that had coalesced and ruptured a left lung bronchus was detected at autopsy. Pathological examination revealed an inflammatory aortic aneurysm.

This paper is concerned with active control of generating a virtual sound image at the designated spot in a free space while producing a zone of quiet in the same free space. The former strategy termed acoustic control and the latter called active noise control seem to contradict, however it is found they are able to coexist without conflict in the same free space of interest. With a view to minimizing a local acoustic power in the desired region, an optimal control law is derived under the constraint such that a desired sound pressure is generated at a target control point. Acoustic potential energy evaluated in the target zone is numerically analyzed, showing a significant attenuation especially at low frequencies may be obtained. Sound pressure over the target space is also numerically analyzed, revealing the noticeable reduction in the zone of quiet is generated, while the desired sound pressure at the control point remains intact. Finally, an experiment using an inverse filtering and filtered-x LMS algorithm is conducted, demonstrating the generation of a quiet zone at the designated region while maintaining the desired sound pressure at the control point.

We report the first case of a chronic intestinal pseudoobstruction (CIPO) in a patient with rheumatoid arthritis (RA) in whom a stoma was constructed at the sigmoid colon to decompress intracolonic pressure. The treatment improved quality of life in this patient, suggesting that surgical resection of the colon to decompress intracolonic pressure would be one of the options for the treatment of intractable CIPO. The resected specimen obtained from the sigmoid colon was found to be palisaded, with nuclei crowded in some areas of the inner circular muscle layer and thickened, with zonal or focal myxoid regions with interstitial fibrosis, composed of collagenous and elastic fibers, in the outer longitudinal muscle layer. Some of the smooth muscle cells in the outer longitudinal muscle layer showed mild degeneration with cytoplasmic vacuolar changes, but no inflammatory changes. However, further studies are required to determine whether these histopathological changes are unique to RA.

The applicability of monitoring concentrations of serum KL-6 and serum surfactant protein-D (SP-D) in the detection of methotrexate-associated lung injury (MTX pneumonitis) in patients with rheumatoid arthritis (RA) was investigated. The concentrations of these markers, sequentially measured in two patients with RA complicated with MTX pneumonitis, were increased in accordance with the severity of MTX pneumonitis. Conversely, the concentrations of these markers were decreased with the improvement of MTX pneumonitis, suggesting that the monitoring of these markers could be applicable not only for detecting the onset of MTX pneumonitis, but also for detecting the therapeutic response of MTX pneumonitis.

Objective—To examine the eVect of transfection of oligodeoxynucleotides (ODNs) containing a CpG motif (CpG-ODN), of which the sequence was derived from circulating DNA in the sera of patients with systemic lupus erythematosus (SLE), on the expression of intercellular adhesion molecule-1 (ICAM-1) and synthesis of mRNA for proinflammatory cytokines and ICAM-1 in human umbilical vein endothelial cells (EC). Methods—A CpG-ODN or a control analogue, GpC-ODN, was transfected into EC. ICAM-1 expression was examined by flow cytometry, and expression of mRNA in EC encoding interleukin 1 (IL1), IL6, IL8, tumour necrosis factor AE (TNFAE), interferon a (IFNa), and ICAM-1 was examined by semiquantitative reverse transcriptase-polymerase chain reaction. Results—The CpG-ODN augmented the expression of ICAM-1 on EC determined by flow cytometry and increased mRNA levels of IL6, IL8, TNFAE, IFNa, and ICAM-1, but the GpC-ODN did not. Conclusion—Synthesised DNA, with a sequence corresponding to that of the fragment containing the CpG motif, in sera of patients with SLE was found to enhance ICAM-1 expression on EC, suggesting the participation of circulating DNA fragments in the pathogenesis of vasculitis in SLE. (Ann Rheum Dis 2001;60:685‐689)

To determine the significance of serotonin in the pathogenesis of interleukin (IL) 6-induced pulmonary hypertension (IL-6-PH) in rats, the plasma serotonin concentrations, and the effects of a specific antagonist of the serotonin (5-hydroxytryptamine [5-HT]) receptor, 1-[o-(m-methoxyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-propyl hydrogen succinate hydrochloride (MCI) on the degree of pulmonary hypertension (PH) were investigated in MCI-treated IL-6-PH (IL-6-MCI-PH) rats.The thickness of the media of small pulmonary arteries and the ratio of the weight of the right ventricle free wall (RV) to that of the left ventricle with the septum (LV + S) were measured as indexes of the degree of PH. Serotonin concentrations in plasma and in supernatants of cultured vascular smooth muscle cells (VSMCs) stimulated by IL-6 were measured by high-performance liquid chromatography. The amplification of DNA encoding the 5-HT receptor in the lung specimen and VSMCs was performed by polymerase chain reaction.The degree of PH, as determined by the medial thickness of small pulmonary arteries, was significantly increased in IL-6-PH rats as compared with normal control rats (p0.05), and that in IL-6-MCI-PH rats was not significantly different from that in normal control rats. The RV/LV + S weight ratio in the IL-6-PH rats was significantly higher than that in normal control rats (p0.01). The RV/LV + S weight ratio in IL-6-MCI-PH rats was significantly lower than that in IL-6-PH rats (p0.01) and was not significantly different from that in normal control rats. The serotonin concentration was significantly higher in IL-6-PH rats than in normal control rats (p0.02), and the serotonin concentration in IL-6-MCI-PH rats was not significantly different from that in the normal control rats. The expression levels of the 5-HT receptor messenger RNA in the lung tissue tended to increase in IL-6-PH rats but was suppressed in IL-6-MCI-PH rats. IL-6 significantly increased the amount of serotonin released from VSMCs (p0.02). The expression of the 5-HT receptor messenger RNA was observed with IL-6 stimulation as was observed with serotonin stimulation in VSMCs.Serotonin receptor antagonists could be considered as potentially useful agents for the treatment of chronic thromboembolic PH, as well as for that of primary PH and PH associated with collagen vascular diseases.

A 38-year-old woman visited our hospital with edema on her face and conjunctivae. The underlying disease was not clarified, and she did not visit the hospital afterwards. She suffered from diarrhea, polyarthralgia, Raynaud's phenomenon, malar rash and hair loss in the subsequent two years, and was hospitalized because of hypoproteinemia. Her urine, liver and heart test results did not account for her hypoproteinemia. She was diagnosed as having protein-losing enteropathy (PLE) associated with SLE based on the 99mtechnetium-labeled human serum albumin scintigraphy findings, clinical findings and laboratory results of antinuclear and anti-Sm antibodies. This case report demonstrates a strong association between PLE and SLE because PLE was aggravated along with the appearance of SLE symptoms and PLE subsided with prednisolone treatment along with improvement of SLE.(Internal Medicine 40: 449-453, 2001)

The initial presentation of a patient with Wegener's granulomatosis was indistinguishable from that of Henoch-Schönlein purpura. The patient presented with skin purpura and pulmonary hemorrhage followed by purpura in the colon. The diagnosis of this patient at that time was Henoch-Schönlein purpura. With time, massive lesions in the sinus and those with cavities in the lung became apparent, and a specimen obtained from the sinus massive lesion was disclosed to be granulomatous inflammation. Retrospectively, the proteinase 3 antineutrophil cytoplasmic antibody turned out to be strongly positive in her stored serum from the time of the initial presentation.

OBJECTIVE To investigate the effects of an intradermal injection of an unmethylated oligodeoxynucleotide (ODN) containing CpG motifs on the severity of collagen-induced arthritis (CIA). METHODS CIA was induced in DBA/1 LacJ mice by immunization with bovine type II collagen (CII) in Freund's complete adjuvant followed 3 weeks later by immunization with CII in Freund's incomplete adjuvant (yielding CIA mice). Unmethylated ODN containing a CpG motif was injected intradermally into DBA/1 LacJ mice at a dosage of 20 microg (yielding CpG-CIA mice) 1 week prior to the first immunization with CII. Unmethylated ODN containing a GpC motif instead of a CpG motif and ODN containing a methylated CpG motif were used to produce controls (GpC-CIA mice and mCpG-CIA mice, respectively). After the second immunization with CII, arthritis scores were measured weekly up to the eighth week. At the eighth week, the mice were killed, histopathologic changes in the ankle joints were examined, and titers of interferon-gamma (IFNgamma) in the supernatants of splenocytes (1 x 10(7)) stimulated in culture by CII for 3 days were determined by enzyme-linked immunosorbent assay. RESULTS CpG-CIA mice had significantly higher arthritis scores than CIA mice. CpG-CIA mice had more severe histopathologic changes than CIA mice and mCpG-CIA mice. Moreover, splenocytes in CpG-CIA mice produced higher IFNgamma titers in response to CII than did splenocytes in CIA mice and mCpG-CIA mice. CONCLUSION Injection of unmethylated oligo-DNA containing CpG motifs aggravated CIA through activation of the Th1-type immune response, suggesting that microbial infection could be one of the mechanisms for aggravation or exacerbation of arthritis or, alternatively, that such infection could be an adjuvant in the induction of arthritis in rheumatoid arthritis.

The presence of perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCAs) and that of antibodies against cathepsin G, a target antigen for P-ANCAs, was determined in the sera of patients with ulcerative colitis (UC), relative to the endoscopic severity and disease activity. P-ANCAs were detected by indirect immunofluorescent assay (IIF) on ethanol-fixed human neutrophils. Antibodies to cathepsin G were detected by an enzyme-linked immunosorbent assay (ELISA) and Western blotting. P-ANCAs were detected by IIF in 62.5% of 32 patients with active UC. Anti-cathepsin G antibodies were detected in 40.6% of 32 patients with active UC, and their prevalence was significantly higher in patients with severe colitis, as determined by endoscopy, than in those with mild or moderate colitis (P < 0.05). The prevalence and titers of anti-cathepsin G antibodies were significantly higher during the active than the inactive phase of the disease (P < 0.05). Measurement of titers of anti-cathepsin G antibodies by ELISA in the serum is useful for evaluating the activity of UC.

Endogenous retroviral gene products have been recognized as being expressed in human cancerous tissues. However, these products have not been shown to be antigenic targets for T-cells, possibly due to immune tolerance. Since carcinogen-induced colon tumor CT26 expresses an envelope protein, gp70, of an endogenous ecotropic murine leukemia virus that is comparable to human tumor-associated antigens, we examined whether a DNA vaccine containing the gp70 gene induces protective immunity against CT26 cells. Injection of mice with plasmid DNA (pDNA) encoding gp70 alone failed to induce anti-gp70 antibody (Ab) or anti-CT26 cytotoxic T lymphocyte (CTL) responses. However, immunization with pDNA encoding the beta-galactosidase (beta-gal)/gp70 fusion protein induced anti-gp70 Ab and anti-CT26 CTL responses and conferred protective immunity against CT26 cells. These results indicate that beta-gal acts as an immunogenic carrier protein that helps in the induction of immune responses against the poorly immunogenic gp70. Considering these results, it is possible that potential tolerance to the endogenous retroviral gene products expressed by human tumors may be overcome by DNA vaccines that contain an endogenous retroviral gene fused to genes encoding immunogenic carrier proteins.