Search

The structure elucidation and biological activity of novel YM-254890 (1) analogues and semi-synthetic derivatives are described. Three natural analogues, YM-254891 (2), YM-254892 (3), and YM-280193 (4), were isolated from the fermentation broth of Chromobacterium sp. QS3666, and two hydrogenated derivatives, YM-385780 (5) and YM-385781 (6), were synthesized from YM-254890. Their structures were determined by one- and two-dimensional NMR studies and mass spectrometry. Among these compounds, two natural analogues 2–3 which possessed acyl groups at β-HyLeu-1 and one derivative 6 whose conformation was similar to that of 1 showed comparable Gαq/11 inhibitory activity to that of 1. This indicates that the acyl β-HyLeu residue plays an important role in activity and also that the α,β-unsaturated carbonyl group of the N-MeDha residue is not critical to activity. The other hydrogenated derivative 5 had significantly less activity, which could be attributed to conformational differences. [Copyright &y& Elsevier]

The isolation and structure elucidation of YM-254890, a novel Gq/11 inhibitor from Chromobacterium sp. QS3666, is described. The gross structure was determined by one- and two-dimensional NMR studies and mass spectrometry. YM-254890 is a cyclic depsipeptide containing uncommon amino acids; β-hydroxyleucine (two residues), N,O-dimethylthreonine and N-methyldehydroalanine. YM-254890 exists as a mixture of two conformers in a variety of NMR solvents, and the distinction between major and minor conformers appears to lie in the geometry of the amide bond between 3-phenyllactic acid and N-methyldehydroalanine. The absolute stereochemistery was elucidated by Marfey''s analysis and chiral HPLC analysis of the acid hydrolysate of YM-254890. [Copyright &y& Elsevier]

The prognosis of microscopic polyangiitis (MPA) with interstitial lung disease (ILD) is significantly worse than that of MPA without ILD. However, the clinical characteristics in MPA-ILD, especially poor prognostic factors, are not elucidated. We evaluated demographic, clinical, laboratory, and radiological findings, treatments, and outcomes of 80 patients with MPA, and investigated prognostic factors of respiratory-related death in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) positive MPA-ILD. Ground-glass opacity and fibrosis were evaluated as scores on high-resolution computed tomography (HRCT). The presence of ILD was consistent with a high risk of respiratory-related death (hazard ratio, 4.8; P = 0.04). Multivariable logistic regression analyses using propensity scoring showed right or left lower lobe fibrosis score to be significantly associated with respiratory-related death (P = 0.0005 and 0.0045, respectively). A right or left lower lobe fibrosis score ≥ 2, indicating the presence of honeycombing at 1 cm above the diaphragm, was determined to be the best cut-off value indicating a poor prognosis. The 5-year survival rate was significantly lower in patients with right or left lower lobe fibrosis score ≥ 2 (survival rates: 37% and 19%, respectively) than those with a score < 2 (71% and 68%, respectively) (P = 0.002 and 0.0007, respectively). These findings suggest that the presence of honeycomb lesions in bilateral lower lobes on chest HRCT was associated with respiratory-related death in patients with MPO-ANCA positive MPA-ILD. [ABSTRACT FROM AUTHOR]

Objectives: 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. Method: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Objectives To elucidate the serum cytokine profile and address the pathomechanism of interstitial lung disease (ILD) complicated with PM/DM. Methods Forty patients with PM/DM-ILD were enrolled, and principal components analysis and cluster analysis were performed to classify patients into subgroups. Additionally, we compared cytokine profiles between the survivors and dead patients and between anti-melanoma differentiation-associated gene 5 antibody- and anti-aminoacyl tRNA synthetase antibody-positive ILD patients. We also examined the association of various cytokines with disease activity indicators and prognosis of ILD. Results The principal components analysis data allowed classification of the cytokine profile into three groups: group 1, neutrophilic and M1-macrophage-driven cytokines; group 2, type 1 Th cell-driven and M2-macrophage-induced cytokines; and group 3, M2-macrophage-driven cytokines. Cluster analysis showed the presence of PM/DM-ILD patient groups with high or low levels of total cytokines. Ninety percent of patients who died of ILD were included in clusters with high cytokine levels. Serum cytokine levels of all groups were significantly higher in the anti-melanoma differentiation-associated gene 5 antibody-positive patients than in the anti-aminoacyl tRNA synthetase antibody-positive patients. Groups 1 and 2 significantly correlated with known factors for poor prognosis, such as serum ferritin levels and alveolar-arterial oxygen difference. Serum cytokine levels of patients in group 1 were significantly higher initially and at 2 and 4 weeks in those who died. Conclusion These findings suggested that the activation of monocytes, macrophages and type 1 Th cells, and neutrophils play roles in the pathomechanism of PM/DM-ILD, and group 1 cytokines could be useful biomarkers for predicting prognosis of PM/DM-ILD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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<0.001)], toxic adverse events [from 79.3% (IFX) to 95.4% (ABT), Cox P = 0.043], and remission [from 94.2% (TCZ) to 100.0% (CZP), Cox P = 0.58]. Finally, overall retention rates excluding non-toxic reasons and remission for discontinuation ranged from 50.0% (ETN) to 78.1% (ABT) (Cox P<0.001). Conclusions: ABT showed lowest discontinuation rate by lack of effectiveness and by toxic adverse events, which lead to highest overall retention rates (excluding non-toxic reasons and remission) among seven bDMARDs in adjusted model of elderly RA patients. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether remission can be sustained for rheumatoid arthritis (RA) patients after tapering abatacept (ABT). Method: All patients were naïve to biological disease‐modifying anti‐rheumatic drugs (bDMARDs) and in low or moderate Disease Activity Score of 28 joints with C‐reactive protein (DAS)28‐CRP). ABT was administrated intravenously (IV) or subcutaneously (SC) for 36 weeks to patients with RA, who had not previously received bDMARDs. As the ABT tapering protocol, ABT was administrated SC at 125 mg every 2 weeks for 12 weeks in patients with remission. RA disease activity was assessed by DAS28‐CRP and ultrasonography. Remission was assessed by defining it as DAS28‐CRP <2.3. Results: Of the 51 patients, 84.3% were women (mean age 68.7 ± 10.2 years, mean disease duration 7.7 ± 10.2 years). Twenty‐nine patients achieved remission and a power Doppler (PD) score ≤1 at each joint at 36 weeks, followed by tapering ABT. Of these patients, 25 sustained DAS28‐CRP remission, and DAS28‐CRP was not significantly elevated (1.62 ± 0.41 to 1.69 ± 0.49) at 48 weeks, but the total PD score was significantly elevated (1.52 ± 1.21 to 2.59 ± 2.81 P = 0.049). Longer disease duration, higher DAS28‐CRP at 24 weeks, and higher total PD score at 24 weeks were predictors of an elevated total PD score after tapering ABT therapy. Conclusion: These findings suggest that ABT tapering is a promising short‐term strategy to sustain remission in patients with RA, and ultrasonography is a useful tool for monitoring disease activity after tapering ABT. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The efficacy and safety of liposomal amphotericin B (L-AMB) in the treatment of invasive fungal infections (IFIs) were retrospectively evaluated for patients with connective tissue diseases (CTDs) during treatment with immunosuppressive therapy. Subjects were 13 patients with CTDs complicated by IFI, on the basis of clinical symptoms, imaging findings, and microbiological and histological examinations. All patients were treated with L-AMB. Efficacy and safety were evaluated before and after administration of L-AMB. Underlying diseases were systemic lupus erythematosus for 4 patients, rheumatoid arthritis for 3, microscopic polyangiitis for 2, adult-onset Still disease for 1, dermatomyositis for 1, and mixed connective tissue disease for 1. Eight patients were resistant to other antifungal drugs. Prednisolone was given to 11 patients and the median dose was 10 mg/day. Immunosuppressants were used for 8 patients. The median duration of administration of L-AMB was 8.5 days (range 4-38 days). In proven and probable diagnosis patients ( n = 5), the treatment was effective for 3 patients and ineffective for 2 (efficacy rate 60 %). Serum 1,3-β- d-glucan antigenemia (BG) levels decreased after treatment in the 2 patients who were positive for BG. Serum Aspergillus galactomannan antigen levels decreased in 3 of 4 patients with Aspergillus infection. No patient died of IFI. Regarding potential adverse reactions, there were no significant changes in serum creatinine and potassium levels. L-AMB is effective and well-tolerated for treatment of IFI in patients with CTDs. [ABSTRACT FROM AUTHOR]

We retrospectively examined the effect of combination therapy with prednisolone and cyclosporin-A (CSA) on the findings of pulmonary function tests (PFTs) and chest high-resolution computed tomography (HRCTs) scans in patients with dermatomyositis (DM) and acute/subacute interstitial pneumonia (A/SIP). We also examined whether CSA therapy improved PFT and chest HRCT findings. DM patients ( n = 14) with A/SIP were treated with 1 mg/kg/day prednisolone and 4 mg/kg/day CSA within 4.4 days (range, 1-12 days) from diagnosis. The trough level (C0) and 2-h post-dose blood concentration (C2) of CSA were measured. PFTs and HRCT scans were performed before and 1 year after treatment. The total ground-glass opacity area was calculated with the HRCT findings and used as the CT score. Combination prednisolone and CSA therapy improved the TLC%, VC%, FVC%, EFV1.0%, and CT score ( P = 0.027, 0.003, 0.002, 0.001, and 0.001, respectively). The C0 level was 178.8 ng/ml (range, 71-456 ng/ml), and the C2 level was 1,336.6 ng/ml (range, 814-2,873 ng/ml). Therapeutic changes in FVC%, FEV1.0%, and DLCO% were correlated with the C2 CSA level ( P = 0.047, 0.025, and 0.035, respectively). However, the PFT results and CT scan scores did not correlate with the daily dose or C0 level of CSA. Improvements in the CT score were correlated with time from IP diagnosis to CSA initiation ( P = 0.014). Early intervention with prednisolone and CSA combination therapy and tight control of the daily CSA dose by monitoring the C2 level improved PFT and chest HRCT findings in DM-A/SIP. [ABSTRACT FROM AUTHOR]

Objectives: The impact of individual biological/targeted synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) on kidney function in patients with rheumatoid arthritis (RA) remains unclear. This study aimed to determine the comparative effects of b/tsDMARDs on chronic kidney disease (CKD) incidence in patients with RA., Methods: This multicentre cohort study included patients with RA who had baseline estimated glomerular filtration rate (eGFR) of ≥ 60 mL/min/1.73 m2 and started a tumor necrosis factor inhibitor (TNFi), cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig), interleukin-6 receptor inhibitor (IL-6Ri), or Janus kinase inhibitor (JAKi) in Japan. Multiple propensity score-based inverse probability weighting (IPW) was used to adjust confounders. The incidence of CKD was compared among b/tsDMARDs using IPW mixed-effect Cox proportional hazards models and linear mixed-effect models with IPW examined trajectories of eGFR., Results: Among 2187 patients with 3068 treatment courses and up to 11 years of follow-up, CKD occurred in 275 cases. Compared with the CTLA4-Ig group, the TNFi group had a significantly lower CKD incidence (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.46-0.97, p= 0.04), whereas the JAKi group had a significantly higher incidence (HR 2.16, 95% CI 1.23-3.79, p= 0.01). The trajectory of eGFR was significantly greater in the JAKi group than in the CTLA4-Ig group (CTLA4-Ig: -1.28 mL/min/1.73 m2/year, JAKi: -2.29 mL/min/1.73 m2/year, p< 0.001)., Conclusions: TNFi use was associated with reduced CKD incidence, whereas JAKi showed a less protective association for kidney function in patients with RA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: To investigate the association of large joint involvement (LJI) with disease activity and drug retention in patients with rheumatoid arthritis (RA) who started receiving a biological disease-modifying antirheumatic drug or Janus kinase inhibitor., Methods: Patients with RA from a Japanese multicenter observational registry were enrolled. Our definition of large joints included the shoulder, elbow, hip, knee, and ankle joints. Linear mixed-effects models were used to examine changes in the clinical disease activity index (CDAI) score at Week 24 as the primary outcome, and drug retention rates were compared between patients with and without LJI using Cox proportional hazards models. We examined the potential effect modifications of changes in the CDAI by baseline characteristics., Results: Overall, 2507 treatment courses from 1721 patients were included (LJI, 1744; no LJI, 763). Although LJI was associated with significantly higher changes in CDAI from baseline at Week 24 (difference in change in CDAI: -5.84 [-6.65 to -5.03], p < .001), CDAI was significantly higher in patients with LJI over time. Retention rates were similar in both groups. The association of LJI with changes in disease activity was more prominent in patients with a short disease duration, negative anti-citrullinated peptide antibodies, and interleukin-6 receptor inhibitor (IL-6Ri) use., Conclusion: Although LJI was associated with a greater reduction in disease activity from baseline, higher disease activity at baseline was not offset over time in patients with LJI, demonstrating that LJI is an unfavorable predictor. An early treat-to-target strategy using an IL-6Ri may be beneficial for patients with LJI., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

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 < .0001). Long-term increase in serum KL-6 levels is associated with respiratory-disease related death in patients with RA-ILD., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: This multicentre retrospective study in Japan aimed to assess the retention of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors (JAKi), and to clarify the factors affecting their retention in a real-world cohort of patients with rheumatoid arthritis., Methods: The study included 6666 treatment courses (bDMARD-naïve or JAKi-naïve cases, 55.4%; tumour necrosis factor inhibitors (TNFi) = 3577; anti-interleukin-6 receptor antibodies (aIL-6R) = 1497; cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig) = 1139; JAKi=453 cases). The reasons for discontinuation were divided into four categories (ineffectiveness, toxic adverse events, non-toxic reasons and remission); multivariate Cox proportional hazards modelling by potential confounders was used to analyse the HRs of treatment discontinuation., Results: TNFi (HR=1.93, 95% CI: 1.69 to 2.19), CTLA4-Ig (HR=1.42, 95% CI: 1.20 to 1.67) and JAKi (HR=1.29, 95% CI: 1.03 to 1.63) showed a higher discontinuation rate due to ineffectiveness than aIL-6R. TNFi (HR=1.28, 95% CI: 1.05 to 1.56) and aIL-6R (HR=1.27, 95% CI: 1.03 to 1.57) showed a higher discontinuation rate due to toxic adverse events than CTLA4-Ig. Concomitant use of oral glucocorticoids (GCs) at baseline was associated with higher discontinuation rate due to ineffectiveness in TNFi (HR=1.24, 95% CI: 1.09 to 1.41), as well as toxic adverse events in JAKi (HR=2.30, 95% CI: 1.23 to 4.28) and TNFi (HR=1.29, 95%CI: 1.07 to 1.55)., Conclusions: TNFi (HR=1.52, 95% CI: 1.37 to 1.68) and CTLA4-Ig (HR=1.14, 95% CI: 1.00 to 1.30) showed a higher overall drug discontinuation rate, excluding non-toxicity and remission, than aIL-6R., Competing Interests: Competing interests: KE is affiliated with the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho. KE has received research grants from AbbVie, Asahi-Kasei, Eisai, Mitsubishi-Tanabe and Teijin Pharma. KE has received a speaker fee from AbbVie, Amgen, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Pfizer, Sanofi, Taisho and UCB Japan. YE received a research grant from Eli Lilly. YM received a research grant from Eli Lilly, and speaker fee from Eli Lilly, Chugai, Pfizer, Bristol-Myers Squibb and Mitsubishi-Tanabe. YO received a speaker fee from Chugai, Ono Pharmaceutical and Pfizer. MaH received a speaker fee from Astellas, Ayumi, Eli Lilly, Mitsubishi-Tanabe, Ono Pharmaceutical, Pfizer and Takeda. MoH received a research grant from Mitsubishi-Tanabe, Eisai, Eli Lilly, Bristol-Myers Squibb and Novartis Pharma, and a speaker fee from Mitsubishi-Tanabe, Eisai, Eli Lilly, Bristol-Myers Squibb and Novartis Pharma. KM is affiliated with a department that is financially supported by four pharmaceutical companies (Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Ayumi and UCB Japan) and the city government (Nagahama City), and received a research grant from Daiichi-Sankyo and speaker fee from AbbVie, Asahi-Kasei, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Bristol-Myers Squibb and Pfizer. RH received a speaker fee from AbbVie and Eisai. TF is affiliated with a department that is financially supported by four pharmaceutical companies (Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Ayumi and UCB Japan) and the city government (Nagahama City), and received a speaker fee from Asahi-Kasei, AbbVie, Janssen, Mitsubishi-Tanabe and Eisai. TadO received a research grant from AbbVie, Asahi-Kasei, Chugai, Eisai, Eli Lilly and Mitsubishi-Tanabe, and a speaker fee from AbbVie, Chugai, Eli Lilly, Janssen and Novartis Pharma. AK received a research grant from Chugai, and a speaker fee from Chugai, Eisai, Mitsubishi-Tanabe, Abbvie and Ono Pharmaceutical. KN has received a research grant from Astellas, and supervises the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho. WY, KN, YH, YS, HA, TakO, YU, MK, ST, SH and SO have no financial conflicts of interest to disclose concerning this manuscript. These companies had no role in the study design, data collection, data analysis, data interpretation and preparation of the manuscript., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This multicenter retrospective study aimed to clarify the prognostic factors for mortality and changes in treatment modalities and disease activities after the onset of Pneumocystis jirovecii pneumonia (PCP) in patients with rheumatoid arthritis (RA). Data regarding the clinical background, treatment modalities, and disease activity indicators of RA at the onset of PCP (baseline), and 6 months and 12 months after treatment were extracted. Of the 37 patients with RA-PCP (median age, 69 years; 73% female), chemical prophylaxis was administered to 8.1%. Six patients died during PCP treatment. The serum C-reactive protein (CRP) levels and the prednisolone (PDN) dose at baseline in the PCP death group were significantly higher than those in the survivor group. Multivariate analysis using a Cox regression model showed that PDN dose at baseline was a predictor of death from PCP in patients with RA. During the 12 months from baseline, the RA disease activity significantly decreased. A high dose of corticosteroids for RA may result in a poor prognosis when PCP is complicated. In the future, preventive administration techniques must be established for patients with RA who need PCP prevention.

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., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) often causes peripheral nervous system impairments. However, little is known about subclinical involvements of the central nervous system in AAV. We investigated the frequency and progression of cerebral small vessel disease (SVD) in patients with AAV., Methods: This single-center, case-control study comprised 56 patients with myeloperoxidase (MPO)-ANCA-positive AAV. Cerebral SVD presenting periventricular and deep white matter hyperintensities was assessed using brain magnetic resonance imaging (MRI). Seventy-five patients with non-stroke-associated neurological diseases were employed as controls., Results: At clinical diagnosis of MPO-ANCA-positive AAV, the frequency of periventricular hyperintensities in the AAV group was significantly higher than that in the control group (P = 0.014). Shinohara and Fazekas grades of periventricular hyperintensities in the AAV group were significantly higher than those in the control group (P = 0.019 and 0.020, respectively). In the AAV group, atherosclerosis-related factors, such as age and hypertension, were not associated with the Shinohara grades of periventricular hyperintensities, whereas serum CRP levels were significantly associated (odds ratio = 6.000, 95% confidence interval 1.648-21.840, P = 0.004). MRI changes were followed in 23 patients with AAV until 2 years after 6 months of diagnosis. Six of these patients worsened the grades of periventricular hyperintensities, while two of 27 in the control group worsened the grades (P = 0.013)., Conclusion: Inflammatory events are associated with the occurrence of cerebral SVD before clinical diagnosis of MPO-ANCA-positive AAV. The patients may be continuously exposed to the risk of cerebral SVD after immunosuppressive therapy.

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 < 0.001)], toxic adverse events [from 81.8% (IFX) to 94.0% (ABT), Cox P < 0.001], and remission [from 92.4% (ADA and IFX) to 97.7% (ETN), Cox P < 0.001]. Finally, overall retention rates excluding non-toxic reasons and remission for discontinuation ranged from 53.4% (IFX) to 75.5% (ABT) (Cox P < 0.001)., Conclusions: TCZ showed the lowest discontinuation rate by lack of effectiveness, ABT showed the lowest discontinuation rate by toxic adverse events, ADA and IFX showed the highest discontinuation rate by remission, and ABT showed the highest overall retention rates (excluding non-toxic reasons and remission) among seven bDMARDs in the adjusted model.

Background: Insufficient narrowing of alar width, alar distortion, and noticeable scarring are commonly encountered after alar base reduction. The authors aimed to demonstrate an alar cinching with subcutaneous flaps procedure to reduce the alar width while controlling the alar axis and sidewall curvature., Methods: A retrospective chart review of 560 patients who underwent alar base reduction between 2000 and 2015 was performed. The clinical outcomes of alar cinching with subcutaneous flaps were compared to those of vestibular floor excision with cinching suture. Mean change in alar width was compared to assess narrowing efficacy between the two groups. In addition, mean changes in interalar distance for the upper, middle, and lower parts of the alae were compared to evaluate the alteration of alar axes., Results: Seventy-three patients who underwent alar base narrowing alone (alar cinching with subcutaneous flaps, n = 42; vestibular floor excision with cinching suture, n = 31) were identified. Alar cinching with subcutaneous flaps was significantly more effective than vestibular floor excision with cinching suture in reducing alar width. In patients with vertical alar axes, alar cinching with subcutaneous flaps achieved more uniform narrowing of the entire alae, resulting in prevention of alar distortion. The incidence of complications after alar cinching with subcutaneous flaps was 5.7 percent., Conclusions: Alar cinching with subcutaneous flaps achieved sufficient narrowing of the nasal base in the long-term follow-up in patients with any type of alar axis and enabled the reduction of sidewall curvature while eliminating the need for wedge resection., Clinical Question/level of Evidence: Therapeutic, III.

Objectives: We retrospectively investigated efficacy and safety of combination therapy with prednisolone (PSL) and tacrolimus (TAC) for progressive interstitial pneumonitis with systemic sclerosis (SSc-PIP)., Methods: We studied 11 patients with SSc-PIP who received combination therapy with PSL (0.5 mg/kg/d) and TAC (3 mg/d)., Results: Baseline Hugh-Jones grades were I, II, III, and IV in 2, 6, 2, and 1 patients, respectively. Krebs von den Lungen-6 (KL-6) values were elevated to 914 (range 300-2614) U/mL. % Diffusing capacity of carbon monoxide (%DLco) remarkably decreased to 47.4 (range 9.7-64.4) %. All patients were alive at 1 year after therapy. In response to treatment, interstitial pneumonia (IP) improved in three patients, stable in seven patients, and deteriorated in one patient. Total ground-glass opacity (GGO) score improved (p = .005). No significant changes occurred in values of KL-6, % forced vital capacity (%FVC), and %DLco. Presently, all seven patients who could be followed up were alive. IP improved in three patients and stable in four patients. Total GGO score improved (p = .016). KL-6, %FVC, and %DLco did not change. Mild cytomegalovirus or herpes zoster infection occurred in two patients. Grade I renal injuries were observed in three and one patient at 1 year and present, respectively., Conclusion: Combination therapy with PSL and TAC appeared to be well tolerated and effective in suppressing the disease activity of SSc-PIP.

Background: Achieving aesthetic results with forehead augmentation procedures remains challenging. We have developed a method of integrated forehead and temporal augmentation using a three-dimensional (3D) printing-assisted methyl methacrylate implant., Objectives: The study objective was to assess the importance of combined temporal augmentation when performing forehead augmentation., Methods: We identified 34 patients (from 2000 to 2010) who underwent forehead augmentation with a methyl methacrylate implant contoured in situ during surgery and 41 patients (from 2010 to 2016) who underwent integrated forehead and temporal augmentation with a prefabricated methyl methacrylate implant. We conducted a retrospective chart review of patient data including operation time, complications, and instances of revision surgery. Two blinded plastic surgeons scored the aesthetic results of the operations on a 4-point scale (1, poor, to 4, excellent) based on preoperative and posttreatment photographs., Results: The integrated augmentation method resulted in a lower frequency of posttreatment implant removal (one [2%] vs. six [18%]; P < .05), a lower frequency of filler injection for touch up (one [2%] vs. six [18%]; P < .05), and higher mean aesthetic scores (3.7 ± 0.5 vs. 2.2 ± 1.0; P < . 001) compared to the forehead augmentation method. There was no statistically significant difference in surgical complications between the two groups., Conclusions: Integrated forehead and temporal augmentation using a 3D printing-assisted methyl methacrylate implant may be the optimal available procedure, enabling the custom fabrication of contours requested by the patient and providing a rejuvenating and balancing effect on facial appearance.

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 < 2.3) at the time of bDMARD discontinuation were included. Serial disease activities and treatment changes were followed up. BFR was considered to have failed if the disease activity exceeded the remission cutoff value or if bDMARDs were restarted., Results: Overall, 181 RA patients were included. BFR was maintained in 21.5% of patients at 1 year after bDMARD discontinuation. BFR was more successfully achieved after discontinuation of anti-tumor necrosis factor (TNF) monoclonal antibodies (TNFi(mAb)) (infliximab, adalimumab, and golimumab), followed by CTLA4-Ig (abatacept), soluble TNF receptor or Fab fragments against TNF fused with polyethylene glycol (etanercept and certolizumab), and anti-interleukin-6 receptor Ab (tocilizumab). After multivariate analysis, sustained remission (> 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.

Two myxobacterial strains (designated B00001(T) and B00002(T)) were isolated from forest soil samples collected from Yakushima Island, Kagoshima, Japan. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strains B00001(T) and B00002(T) respectively formed independent branches within the suborders Cystobacterineae and Sorangiineae and were most closely related to Cystobacter armeniaca DSM 14710(T) (90.4% similarity) and Byssovorax cruenta DSM 14553(T) (91.3%). Neither strain showed typical features of myxobacteria such as bacteriolytic action or fruiting body formation, but both had high DNA G+C contents (66.3-68.3 mol%). Swarming motility was observed in strain B00002(T) only. Cells of both strains were vegetative, chemoheterotrophic, mesophilic, strictly aerobic, Gram-negative, motile rods, and both strains exhibited esterase lipase (C8), leucine arylamidase, naphthol-AS-BI-phosphohydrolase and β-galactosidase activities. Strain B00001(T) contained MK-7 as the predominant respiratory quinone and the major fatty acid was iso-C15:0. In contrast, strain B00002(T) contained MK-8 as the major cellular quinone and the major fatty acids were C16 : 1ω5c and iso-C17 : 0. Based on the phenotypic and genotypic data presented, strains B00001(T) and B00002(T) represent novel genera and species, for which we propose the names Vulgatibacter incomptus gen. nov., sp. nov. and Labilithrix luteola gen. nov., sp. nov., respectively. The type strains of Vulgatibacter incomptus and Labilithrix luteola are B00001(T) ( = NBRC 109945(T) = DSM 27710(T)) and B00002(T) ( = NBRC 109946(T) = DSM 27648(T)), respectively. The new genera are assigned to the new families Vulgatibacteraceae fam. nov. and Labilitrichaceae fam. nov., respectively. In addition, Anaeromyxobacteraceae fam. nov., is proposed to accommodate the genus Anaeromyxobacter, which is related to the genus Vulgatibacter., (© 2014 IUMS.)