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Background:. The deep inferior epigastric perforator (DIEP) flap is a useful tool for breast reconstruction and tends to be transferred into the breast envelope as the buried flap from an aesthetic point of view. However, it is difficult to monitor the blood flow in the buried DIEP flap after reconstructive microsurgery. Near-infrared spectroscopy devices have recently been used for monitoring the blood flow of various organs. NIRO200NX (Hamamatsu Photonics) continuously measures the tissue oxygen index (TOI) and quickly reflects changes in flap blood flow. In this study, we investigated whether and how much the NIRO200NX applies to monitoring the blood flow of the buried flap. Methods:. We included 156 patients who underwent breast reconstruction using a DIEP flap from October 2013 to May 2022, comprising 57 exposed and 99 buried-type DIEP flap cases. We measured TOI using NIRO200NX, in combination with conventional evaluation methods, including color check, pinprick test, and Doppler sound. Results:. A criterion of TOI 50 gave the best evaluations. All the 57 exposed-type flap cases showed no false evaluations, and NIRO200NX performed precise judgment. In 99 buried-type flap cases, NIRO200NX correctly evaluated 96 cases. For those buried-type cases, we found only two false-positive and one false-negative case. The misjudgments by NIRO200NX were likely caused by hematoma. Conclusion:. We propose NIRO200NX as a reliable device for monitoring the blood flow of the DIEP flap and predicting the outcomes of breast reconstruction by the DIEP flap transfer.

Abstract Polymyalgia rheumatica (PMR) is a chronic inflammatory disease characterized by arthralgia and myalgia of the shoulder and hip girdles, and fever. PMR is linked to autoimmune diseases and autoinflammatory disorders. Exome sequencing has revealed the roles of rare variants in some diseases. Causative genes for monogenic autoinflammatory disorders might be candidate genes for the selective exome analysis of PMR. We investigated rare variants in the coding and boundary regions of candidate genes for PMR. Exome sequencing was performed to analyze deleterious rare variants in candidate genes, and the frequencies of the deleterious rare alleles in PMR were compared with those of Japanese population controls. Deleterious rare alleles in the NLRL12 gene were associated with PMR (P = 0.0069, Pc = 0.0415, odds ratio [OR] 4.49, 95% confidence interval [CI] 1.79–11.27). A multigene analysis demonstrated the deleterious rare allele frequency of the candidate genes for autoinflammatory disorders was also increased in PMR (P = 0.0016, OR 3.69, 95%CI 1.81–7.54). The deleterious rare allele frequencies of the candidate genes including NLRP12 were increased in PMR patients, showing links to autoinflammatory disorders in the pathogenesis of PMR.

Cryptotia is a congenital ear deformity characterized by the upper helix buried under the skin of the temporal region. Recurrence and inadequate correction of ear position are major complications following auricle reconstruction. Abnormalities of the auricular muscles are closely associated with cryptotia and considered to be the main cause. However, current corrective procedures focus on provision of additional skin and abnormal auricular muscle correction is considered supplementary. We report a surgical approach focused on the anatomical repositioning of the external auricular muscle insertions and skin cover with a mini flap.Two consecutive patients aged 6 and 14 years with mild cryptotia (minimal auricular cartilage deformity) were treated using this technique with a follow-up duration of 12–25 months. The abnormal insertion of the superior auricular muscle (SAM) to the superior helix was repositioned to its correct anatomical position below the eminence of the triangular fossa, effectively moving the ear posterosuperiorly. No complications occurred postoperatively, the increase in vertical length of the superior helix to the superior ear attachment was 7.8 and 7.9 mm at 6months. Both patients could wear facemasks comfortably without them sliding off and were satisfied with the esthetic results. Total follow-up duration was 3 years in Case 1 and 4.4 years in Case 2.Primary correction of the SAM to its anatomical position may be a useful method for reducing the size of the skin flaps required with minimal donor site morbidity in reconstruction of mild cryptotia.

Abstract In osteoarthritis (OA), synovial pathology may be induced by proteins released from degenerated cartilage. This study was conducted to identify the proteins released from OA cartilage. OA cartilage was obtained from OA knees at macroscopically preserved areas (PRES) and degenerated areas (DEG), while control cartilage (CONT) was collected from non-arthritic knees. Released proteins were obtained from these cartilage samples by repeatedly applying compressive loading, which simulated loading on cartilage in vivo. The released proteins were analyzed comprehensively by antibody array analyses and a quantitative proteomic analysis. For several proteins, the exact amounts released were determined by Luminex assays. The amount of active TGF-β that was released was determined by an assay using genetically-engineered HEK cells. The results of the antibody array and proteomic analyses revealed that various biologically active proteins are released from OA cartilage, particularly from DEG, by loading. The Luminex assay confirmed that several alarmins, complement proteins C3a and C5a, and several angiogenic proteins including FGF-1, FGF-2 and VEGF-A were released in greater amounts from DEG than from CONT. The HEK cell assay indicated that active TGF-β was released from DEG at biologically significant levels. These findings may be helpful in understanding the pathology of OA.

Objective The hallmarks of the chronic inflammatory disease polymyalgia rheumatica (PMR) include pain, and morning stiffness in areas of the neck, shoulder and pelvic girdle. The human leucocyte antigen (HLA) gene was reported to be an important risk factor for PMR, but it has not been analysed precisely, especially in populations other than Europeans.Methods Genotyping of DRB1 and DQB1 was performed in Japanese PMR patients (n=270) and controls (n=413). Associations between allele carrier and genotype frequencies were determined for PMR.Results DRB1*04:05 was associated with a predisposition to PMR (p=0.0006, Pc=0.0193, OR 1.85, 95% CI 1.31 to 2.62). DRB1*09:01 was associated with protection against PMR (p=1.46×10−5, Pc=0.0004, OR 0.40, 95% CI 0.26 to 0.61). A shared epitope (SE) associated with PMR (p=3.07×10−6, OR 2.11, 95% CI 1.54 to 2.88). DQB1*03:03 (p=0.0010, Pc=0.0140, OR 0.52, 95% CI 0.35 to 0.77) was associated with protection against PMR and DQB1*04:01 (p=0.0009, Pc=0.0140, OR 1.82, 95% CI 1.28 to 2.58) was associated with predisposition to PMR. A gene dosage effect was observed for DRB1*09:01 and DQB1*03:03, but not for DRB1*04:05, SE or DQB1*04:01. Haplotype and logistic regression analyses suggested a protective effect for DRB1*09:01.Conclusion This study is the first to demonstrate predisposing associations of DRB1*04:05, SE, and DQB1*04:01, and protective associations of DRB1*09:01 and DQB1*03:03 with PMR in Japanese patients. Our data indicate HLA has predisposing and protective effects on the pathogenesis of PMR.

Abstract Background Individual‐level surrogates are important for management in patients treated for advanced gastric cancer (AGC). This study aimed to comprehensively investigate the correlation of multiple clinical endpoints in the first‐line chemotherapy of AGC. Methods Individual patient data (IPD) were collected from four Japanese Phase III trials comparing S‐1‐based first‐line chemotherapies (SPIRITS, START, GC0301/TOP‐002, and G‐SOX trials). Patients without Response Evaluation Criteria in Solid Tumors (RECIST)‐based radiological assessments were excluded. Spearman's rank correlation coefficient was tested for correlation among overall survival (OS), progression‐free survival (PFS), and postprogression survival (PPS). OS, PFS, and PPS were compared between responders (best response: complete response or partial response) and nonresponders (best response: stable disease or progressive disease). Results The study included a total of 1492 patients. Eighty percent of the patients (n = 1190) received subsequent chemotherapies after the failure of each trial's treatment protocol. PFS moderately correlated with OS (Spearman correlation coefficient = 0.66, p

Abstract Mixed connective tissue disease (MCTD) is a rare systemic autoimmune disease characterized by the production of anti-U1 ribonucleoprotein antibodies and systemic symptoms similar to those of some other autoimmune diseases. HLA-DRB1 polymorphisms are important genetic risk factors for MCTD, but precise associations of DRB1 genotypes with MCTD have not been reported in Japanese people. Genotyping of HLA-DRB1 and -DQB1 was performed in Japanese MCTD patients (n = 116) and controls (n = 413). Associations of specific allele carriers and genotype frequencies with MCTD were analyzed.The following alleles were found to be associated with predisposition to MCTD: HLA-DRB1*04:01 (P = 8.66 × 10–6, Pc = 0.0003, odds ratio [OR] 7.96, 95% confidence interval [CI] 3.13‒20.24) and DRB1*09:01 (P = 0.0189, Pc = 0.5468, OR 1.73, 95% CI 1.12‒2.67). In contrast, the carrier frequency of the DRB1*13:02 allele (P = 0.0032, Pc = 0.0929, OR 0.28, 95% CI 0.11‒0.72) was lower in MCTD patients than in controls. The frequencies of heterozygosity for HLA-DRB1*04:01/*15 (P = 1.88 × 10–7, OR 81.54, 95% CI 4.74‒1402.63) and DRB1*09:01/*15 (P = 0.0061, OR 2.94, 95% CI 1.38‒6.25) were also higher in MCTD patients. Haplotype and logistic regression analyses suggested a predisposing role for HLA-DRB1*04:01, DQB1*03:03, and a protective role for DRB1*13:02. Increased frequencies of HLA-DRB1*04:01/*15 and DRB1*09:01/*15 heterozygous genotypes were found in Japanese MCTD patients.

Abstract Objective Rheumatoid arthritis (RA) is often complicated with chronic lung diseases (CLD), including interstitial lung disease (ILD) and airway disease, which occur as extra-articular manifestations. CLD in RA have been associated with the production of rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA), or anti-carbamylated protein (CarP) antibody. However, few validation studies have been performed thus far. In the present study, we investigated the association of RF, ACPA, and anti-CarP antibodies with RA complicated with CLD. Methods Sera from RA patients with or without CLD were collected. The levels of serum RF, RF immunoglobulin A (IgA), ACPA IgG, ACPA IgA, and ACPA secretory component (SC) were measured using enzyme-linked immunosorbent assay. Results The comparison of RA patients with and without CLD showed that RF IgA was associated with ILD (mean ± standard deviation: 206.6 ± 400.5 vs. 95.0 ± 523.1 U/ml, respectively, P = 1.13 × 10− 8), particularly usual interstitial pneumonia (UIP) (263.5 ± 502.0 U/ml, P = 1.00 × 10− 7). ACPA SC was associated with RA complicated with ILD (mean ± standard deviation: 8.6 ± 25.1 vs. 2.3 ± 3.4 U/ml, respectively, P = 0.0003), particularly nonspecific interstitial pneumonia (NSIP) (10.7 ± 31.5 U/ml, P = 0.0017). Anti-CarP antibodies were associated with RA complicated with ILD (0.042 ± 0.285 vs. 0.003 ± 0.011 U/ml, respectively, P = 1.04X10− 11). Conclusion RF IgA and ACPA SC in RA were associated with UIP and NSIP, respectively, suggesting different specificities in patients with RA. Anti-CarP antibodies were associated with ILD in RA. These results may help elucidate the different pathogeneses of UIP and NSIP in RA.

Background Interstitial lung disease (ILD) occasionally occurs in rheumatoid arthritis (RA) and confers a dismal prognosis. We previously reported that a single-nucleotide variant (SNV) of MUC5B was associated with ILD in RA. However, the pathogenesis of ILD in Japanese patients with RA could not be explained solely by this SNV because its frequency is extremely low in the Japanese population. Here, we examined whether a different idiopathic pulmonary fibrosis susceptibility SNV might be associated with ILD in Japanese patients with RA.Methods Genotyping of rs2609255 (G/T) in FAM13A was conducted in 208 patients with RA with ILD and 420 without chronic lung disease using TaqMan assays.Results A significant association with usual interstitial pneumonia (UIP) in RA was detected for rs2609255 under the allele model (p=0.0092, Pc=0.0276, OR 1.53, 95% CI 1.12 to 2.11) and recessive model for the G allele (p=0.0003, Pc=0.0009, OR 2.63, 95% CI 1.59 to 4.32). FAM13A rs2609255 was significantly associated with UIP in male patients with RA (p=0.0043, OR 3.65, 95% CI 1.52 to 8.73) under the recessive model.Conclusions This study is the first to document an association of rs2609255 with ILD in Japanese patients with RA, implicating it in the pathogenesis of UIP, though studies on the function of rs2609255 are warranted.

LoRa communication protocol using 920 MHz-band has been opened to the public for Internet of Things (IoT) application and a wide variety of telemeter usage since 2017 in Japan. It is expected to be used for collection of scientific observations and monitoring data at Syowa Station. In JARE61, we have investigated the radio environment of the 920 MHz-band, and its possible impact on the ongoing scientific observations in Syowa Station．A member of the wintering team carries a handy transmitter in the nearby area of Syowa Station, East-ongul Island. The transmitter sends GPS location and time data to the receiver (LoRa gateway) located at the roof handrail of the observation building. Six surveys have been conducted, and we confirmed the reachability of the radio signal in and outside of the Syowa Station. The possibilities of the 920 MHz-band application have been suggested to use monitoring station infrastructure and scientific observations.

Abstract Aim Post‐surgical weight loss influences chemotherapy compliance and may be a risk factor for survival. Intake of an oral elemental nutritional supplement (OENS) can reduce weight loss after gastric cancer (GC) surgery. We assessed whether therapy completion levels would increase in patients receiving postoperative adjuvant chemotherapy in combination with an OENS. Methods This was a multicenter, open‐label, single‐arm, phase II study in GC patients who underwent curative total or distal gastrectomy (TG/DG) and received adjuvant S‐1 chemotherapy. The primary endpoint was the S‐1 completion rate for 1 year with a relative performance (RP) value of ≥70%; secondary endpoints included factors affecting the completion rate of S‐1, RP value after eight S‐1 courses, S‐1 and OENS persistence rates, nutritional index, OENS compliance, and safety. Results In 71 efficacy‐evaluable patients, the S‐1 completion rate was 69.0% (TG, 68.0%; DG, 69.6%) and the RP value was 87.5 (TG, 89.1; DG, 87.5). Over eight treatment courses, median persistence rates were 89.0% for S‐1 and 93.8% for the OENS. The mean OENS compliance was 81.8% at the fourth S‐1 course and 52.9% at the eighth course. The incidence of Grade 3 or 4 adverse events was 27.2%, most commonly neutropenia (12.3%). Conclusions The completion rate of S‐1 for 1 year in patients who could take the OENS exceeded the pre‐defined threshold level. Randomized controlled trials are warranted to confirm the role of OENS in adjuvant chemotherapy.

Abstract Objectives The aim of this study is to evaluate the possibility of the autologous platelet-rich plasma (PRP) collection from the cardiopulmonary bypass (CPB) circuit and to evaluate its effect on the aggregative function. Methods For seventy-two patients undergoing cardiac surgery with CPB, an autologous PRP was prepared using the Haemonetics Component Collection System® by drawing blood from the CPB circuit immediately after CPB was established. The blood samples were taken at three points for examination, A: beginning of surgery, B: immediately after heparin reversal with protamine following discontinuation of CPB, C: after the collected autologous PRP was returned to the patient. Platelet count and platelet aggregation ability were analyzed. Results The mean platelet count in autologous PRP was 5.5 (range: 3–14) units. Platelet count decreased by 115.0 (±27.3) × 1000/μl from A to B and increased by 27.3 ± 17.2 (× 1000/μl) from B to C. When platelet aggregation was measured by Adenosine Diphosphate (ADP) 3.0 μM, it decreased by 42.6% ± 12.1% from A to B and increased by 8.7% ± 7.4% from B to C. Conclusions Autologous PRP can be safely collected by drawing blood from the CPB circuit, platelet count and aggregation ability significantly decreased after CPB including autologous PRP collection. Some improvement was detected in the number of the platelets count and platelet aggregation ability by administrating an autologous PRP even if autologous PRP is collected from CPB circuit. Trial registration UMI-CTR, UMIN000023776 . Registered 1 October 2016.

Abstract Background In osteoarthritis (OA), cartilage matrix is lost gradually despite enhanced matrix synthesis by chondrocytes. This paradox may be explained, at least partly, by reduced chondrocyte anabolism in degenerated area of OA cartilage. However, to date, it is not known why chondrocyte anabolism is suppressed in those areas. Methods Cartilage was obtained from control knees and end-stage OA knees in macroscopically preserved areas and degenerated areas, and gene expression was analyzed in respective regions of cartilage using laser capture microdissection and qPCR. For the cartilage protein analysis, cartilage was obtained from preserved areas and degenerated areas of OA knees in pairs, and proteins were extracted using urea buffer. Protein concentrations were determined by Luminex and compared between the areas. Cartilage explants prepared from preserved areas and degenerated areas of OA knees were cultured in the presence or absence of an AKT inhibitor, and the gene expression was evaluated by qPCR. Finally, the expression of SP1 was evaluated in OA and control cartilage, and the significance of Sp1 on the expression of IGF1R and IRS1 was investigated in experiments using primary cultured chondrocytes. Results Within OA cartilage, the expression of IGF-1, IGF-2, IGF1R and IRS1 was reduced in degenerated areas compared to preserved areas, while the expression of all six IGF-binding protein genes examined was enhanced in the former areas. Consistent results were obtained by a protein analysis. In explant culture, the inhibition of AKT signaling abrogated the abundant matrix gene expression in the preserved areas over the degenerated areas, indicating that suppressed matrix synthesis in degenerated areas may be ascribed, at least partly, to attenuated IGF signaling. Within OA cartilage, the expression of Sp1 was considerably reduced in severely degenerated areas compared to preserved areas, which correlated well with the expression of IGF1R and IRS1. In experiments using primary cultured chondrocytes, the expression of IGF1R and IRS1 was enhanced by the induction of Sp1 expression and reduced by the suppression of Sp1 expression. Conclusions The results of this study suggest that attenuated IGF signaling may be responsible, at least partly, for the reduced matrix synthesis in degenerated areas of OA cartilage.

Abstract Autoimmune hepatitis (AIH) is a rare chronic progressive liver disease with autoimmune features. It mainly affects middle-aged women. AIH is occasionally complicated with liver cirrhosis that worsens the prognosis. Genetic and environmental factors are involved in the pathogenesis of AIH. Genetic studies of other diseases have been revealing of pathogenesis and drug efficacy. In this review, we summarize the genetic risk factors for AIH, including human leukocyte antigen (HLA) and non-HLA genes. A genome-wide association study (GWAS) on European AIH revealed the strongest associations to be with single nucleotide variants (SNVs) in HLA. Predisposing alleles for AIH were DRB1*03:01 and DRB1*04:01 in Europeans; DRB1*04:04, DRB1*04:05, and DRB1*13:01 in Latin Americans; and DRB1*04:01 and DRB1*04:05 in Japanese. Other risk SNVs in non-HLA genes for AIH were found by a candidate gene approach, but several SNVs were confirmed in replication studies. Some genetic factors of AIH overlapped with those of other autoimmune diseases. Larger-scale GWASs of other ethnic groups are required. The results of genetic studies might provide an explanation for the phenotypic heterogeneity of AIH and biomarkers for drug responses.

Background: Rheumatoid arthritis (RA) is occasionally complicated with interstitial lung disease (ILD). A recent genome-wide association study of ILD in RA reported an association with the polymorphism rs12702634 in RPA3-UMAD1 . We conducted an association study of this variant with ILD in Japanese RA patients to replicate this association. Methods: Genotyping of rs12702634 was performed in 175 RA with ILD and 411 RA without chronic lung disease. Results: No association was detected for rs12702634 with ILD in RA ( P = .6369, odds ratio [OR] 1.13, 95% confidence interval [CI] 0.72-1.78). Meta-analysis of these data combined with the data from the recent report showed no significant association ( P = .0996, OR 1.52, 95% CI 0.92–2.49). Conclusions: The present study demonstrated no association of RPA3-UMAD1 rs12702634 with ILD in RA, suggesting the heterogeneity of the disease.

OBJECTIVES Coronavirus Disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Serological testing for anti-SARS-CoV-2 nucleocapsid (N) antibodies (Abs) and anti-SARS-CoV-2 spike (S) Abs is performed to detect prior COVID-19 infection. It is still controversial which antibodies are the most sensitive and specific, and which can be detected earliest after infection. Here, we evaluated the results of serological tests of anti-SARS-CoV-2 N and S Abs in Japan. METHODS Symptomatic COVID-19 patients (n = 84) and control patients with rheumatoid arthritis (n = 93) were recruited at Tokyo National Hospital. Anti-SARS-CoV-2 N and S Abs were measured by commercial electrochemiluminescence immunoassays. RESULTS The fraction of patients positive for anti-SARS-CoV-2 N and S Abs was highest >14 days after symptom onset. The frequency of anti-SARS-CoV-2 S Ab positivity at this time (80.4%) tended to be slightly but not significantly lower than anti-SARS-CoV-2 N Ab positivity (84.8%). Optimized cut-off levels for anti-SARS-CoV-2 N and S Ab positivity were lower than the manufacturer's recommended cut-off levels. Using multiple linear regression analyzes with anti-SARS-CoV-2 N and S Abs, we created an Ab-index with high sensitivity. CONCLUSION To increase the sensitivity of serological diagnostic tests for COVID-19, it is suggested that both anti-SARS-CoV-2 N and S Abs should be measured and cut-off levels decreased.

Objectives: The severe acute respiratory syndrome coronavirus 2 causes coronavirus disease 2019. A serological test is conducted to determine prior infection by severe acute respiratory syndrome coronavirus 2. We investigated whether the results of anti-severe acute respiratory syndrome coronavirus 2 antibody tests are modified in patients with rheumatoid arthritis. Methods: Patients in Japan with rheumatoid arthritis were recruited at Sagamihara Hospital from July 2014 to October 2015 ( n = 38; 2014 cohort) and at Tokyo Hospital from June to October 2020 ( n = 93; 2020 cohort). Anti-severe acute respiratory syndrome coronavirus 2 antibodies were measured by electrochemiluminescence immunoassay or immunochromatographic assay. Results: Anti-severe acute respiratory syndrome coronavirus 2 antibodies were not detected in any of the samples from rheumatoid arthritis patients tested by electrochemiluminescence immunoassay. Anti-severe acute respiratory syndrome coronavirus 2 antibodies were detected by immunochromatographic assay in the 3 (7.9%) serum samples in the 2014 cohort and 15 (16.1%) serum samples in the 2020 cohort. The IgM rheumatoid factor levels were increased in rheumatoid arthritis patients with IgM anti-severe acute respiratory syndrome coronavirus 2 antibodies detected by immunochromatographic assay (mean ± standard deviation (IU/ml), 1223.0 ± 1308.7 versus 503.6 ± 1947.2; P = 0.0101). The levels of IgG rheumatoid factor were also upregulated in rheumatoid arthritis patients with IgM anti-severe acute respiratory syndrome coronavirus 2 antibodies detected by immunochromatographic assay (4.0 ± 0.7 versus 2.4 ± 0.9; P = 0.0013). Conclusion: The results of IgM anti-severe acute respiratory syndrome coronavirus 2 antibody testing by immunochromatographic assay are modified by IgM or IgG rheumatoid factors in rheumatoid arthritis patients.

Chronic lung diseases (CLD), including interstitial lung disease (ILD) and airway diseases (ADs), are common complications of rheumatoid arthritis (RA). Rheumatoid factor (RF) and anti-citrullinated peptide antibodies are reported to be associated with CLD in RA patients. The presence of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies (Abs) is associated with clinically amyopathic dermatomyositis developing into rapidly progressive ILD. However, few studies on anti-MDA5 Abs in RA have been published. Here, we analyzed the association of anti-MDA5 Abs with CLD complications in RA. Anti-MDA5 Abs were quantified in sera from RA patients with or without CLD. Anti-MDA5 Ab levels were higher in RA patients with ADs than without (mean ± SDM, 4.4 ± 2.4 vs. 4.0 ± 4.2, p = 0.0001). AUC values of anti-MDA5 Ab and RF ROC curves were similar in RA patients with or without CLD (0.578, 95%CI 0.530–0.627 and 0.579, 95%CI 0.530–0.627, respectively, p = 0.9411). Multiple logistic regression analysis of anti-MDA5 Abs and clinical characteristics yielded an MDA5-index with a higher AUC value than anti-MDA5 Ab alone (0.694, 95%CI 0.648–0.740, p = 5.08 × 10−5). Anti-MDA5 Abs were associated with ADs in RA patients and could represent a biomarker for CLD, similar to RF. The involvement of anti-MDA5 Abs in the pathogenesis of ADs in RA is proposed.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019. Anti-SARS-CoV-2 spike (S) and neutralizing antibodies (Abs) are measured to evaluate the efficacy of vaccines. Human leukocyte antigen (HLA) may be associated with vaccine efficacy. Here, we investigated the association of HLA polymorphisms with the production of anti-SARS-CoV-2 S or neutralizing Abs in vaccinated rheumatoid arthritis (RA) patients in Japan. Genotyping of DRB1 and DQB1 was conducted in 87 Japanese RA patients vaccinated with BNT162b2. Associations of allele or haplotype carrier frequencies with anti-SARS-CoV-2 S or neutralizing Abs were examined. DRB1*12:01 was significantly positively associated with the production of S Ab (p = 0.0225, odds ratio [OR] 6.08, 95% confidence interval [CI] 1.32–28.03). The DQB1*03:01 allele carrier frequency tended to be higher in high responders of S Ab. Allele carrier frequencies of DRB1*15:01 (p = 0.0102, OR 9.26, 95% CI 1.65–52.01) and DQB1*06:02 (p = 0.0373, OR 7.00, 95% CI 1.18–41.36) were higher in responders of neutralizing Ab. Haplotype and two-locus analyses of DRB1 and DQB1 suggested that DRB1 alleles were the primary drivers of these associations. Logistic regression analysis showed associations of these alleles independent of clinical characteristics. Independent associations were found between HLA alleles and anti-SARS-CoV-2 Ab production by vaccinated RA patients.

Abstract Background In osteoarthritis (OA), cartilage matrix is lost despite vigorous chondrocyte anabolism. In this study, we attempted to determine whether altered matrix synthesis is involved in this paradox in disease progression through gene expression analysis and ultrastructural analysis of collagen fibrils within the cartilage matrix. Methods Cartilage tissues were obtained from 29 end-stage OA knees and 11 control knees. First, cDNA microarray analysis was performed and the expression of 9 genes involved in collagen fibrillogenesis was compared between OA and control cartilages. Then their expression was investigated in further detail by a quantitative polymerase chain reaction (qPCR) analysis combined with laser capture microdissection. Finally, collagen fibril formation was compared between OA and control cartilage by transmission electron microscopy. Results The result of the microarray analysis suggested that the expression of type IX and type XI collagens and fibrillogenesis-related small leucine-rich proteoglycans (SLRPs) may be reduced in OA cartilage relative to the type II collagen expression. The qPCR analysis confirmed these results and further indicated that the relative reduction in the minor collagen and SLRP expression may be more obvious in degenerated areas of OA cartilage. An ultrastructural analysis suggested that thicker collagen fibrils may be formed by OA chondrocytes possibly through reduction in the minor collagen and SLRP expression. Conclusions This may be the first study to report the possibility of altered collagen fibrillogenesis in OA cartilage. Disturbance in collagen fibril formation may be a previously unidentified mechanism underlying the loss of cartilage matrix in OA.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A serological test is used to assess the efficacy of vaccination. It has been reported that anti-SARS-CoV-2 spike (S) and neutralizing antibody (Ab) levels are lower following vaccination in patients with rheumatic disease. Here, we investigated anti-SARS-CoV-2 S and neutralizing Abs in vaccinated rheumatoid arthritis (RA) patients in Japan. Anti-SARS-CoV-2 S and neutralizing Abs were quantified in 101 RA patients and 117 controls. Anti-SARS-CoV-2 S Ab levels were lower in RA patients than both earlier after vaccination in controls (mean RA 324.1 ± 591.8 SDM vs. control 1216.6 ± 854.4 [U/mL], p < 0.0001) and later after vaccination (324.1 ± 591.8 vs. 582.0 ± 415.6 [U/mL], p = 0.0002). The interval between vaccination of the RA patients and serum collection was longer than for controls early after vaccination (142.1 ± 31.6 vs. 98.3 ± 11.2 [days], p < 0.0001), but shorter than the later sample from the controls (142.1 ± 31.6 vs. 257.3 ± 11.2 [days], p < 0.0001). Importantly, anti-SARS-CoV-2 neutralizing Ab titers in RA patients were higher than in either early or later control samples (10.7 ± 4.9 vs. 8.6 ± 6.6 [%], p = 0.0072, and 10.7 ± 4.9 vs. 3.1 ± 3.7 [%], p < 0.0001, respectively). Anti-SARS-CoV-2 S Ab titers in vaccinated RA patients were lower than in controls, but they were influenced by other clinical manifestations. Anti-SARS-CoV-2 neutralizing Ab levels were independently increased in RA.

Interstitial lung disease (ILD) is frequently a complication of rheumatoid arthritis (RA) as an extra-articular manifestation which has a poor prognosis. Acute-onset diffuse ILD (AoDILD) occasionally occurs in RA and includes acute exacerbation of ILD, drug-induced ILD, and Pneumocystis pneumonia. AoDILD also confers a poor prognosis in RA. Previously-established biomarkers for ILD include Krebs von den lungen-6 and surfactant protein-D originally defined in patients with idiopathic pulmonary fibrosis; the sensitivity of these markers for RA-associated ILD (RA-ILD) is low. Although many studies on ILD markers have been performed in idiopathic pulmonary fibrosis, only a few validation studies in RA-ILD or AoDILD have been reported. Biomarkers for RA-ILD and AoDILD are thus still required. Recently, genomic, cytokine, antibody, and metabolomic profiles of RA-ILD or AoDILD have been investigated with the aim of improving biomarkers. In this review, we summarize current preliminary data on these potential biomarkers for RA-ILD or AoDILD. The development of biomarkers on RA-ILD has only just begun. When validated, such candidate biomarkers will provide valuable information on pathogenesis, prognosis, and drug responses in RA-ILD in future.

Versican is a large proteoglycan in the extracellular matrix. During embryonic stages, it plays a crucial role in the development of cartilage, heart, and dermis. Previously, we reported that Prx1-Vcan conditional knockout mice, lacking Vcan expression in mesenchymal condensation areas of the limb bud, show the impaired joint formation and delayed cartilage development. Here, we investigated their phenotype in adults and found that they develop swelling of the knee joint. Histologically, their newborn joint exhibited impaired formation of both anterior and posterior cruciate ligaments. Immunostaining revealed a decrease in scleraxis-positive cells in both articular cartilage and ligament of Prx1-Vcan knee joint, spotty patterns of type I collagen, and the presence of type II collagen concomitant with the absence of versican expression. These results suggest that versican expression during the perinatal period is required for cruciate ligaments' formation and that its depletion affects joint function in later ages.

Serological detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N), spike (S), and neutralizing antibodies (Abs) is commonly undertaken to evaluate the efficacy of vaccination. However, the relative efficiency of different SARS-CoV-2 Ab detection systems has not been extensively investigated. Here, we evaluated serological test systems in vaccinated Japanese. SARS-CoV-2 N, S, and neutralizing Abs in sera of 375 healthy subjects a mean 253 days after vaccination were assessed. The sensitivity of Elecsys Anti-SARS-CoV-2 S (Roche S) and Anti-SARS-CoV-2 S IgG (Fujirebio S) was 100% and 98.9%, respectively, with a specificity of 100% for both. The sensitivity of Anti-SARS-CoV-2 neutralizing Ab (MBL Neu) was 2.7%, and the specificity was 100%. Fujirebio S correlated with Roche S (rho = 0.9182, p = 3.97 × 10−152). Fujirebio S (rho = 0.1295, p = 0.0121) and Roche S (rho = 0.1232, p = 0.0170) correlated weakly with MBL Neu. However, Roche S did correlate with MBL Neu in patients with COVID-19 (rho = 0.8299, p = 1.01 × 10−12) and in healthy subjects more recently after vaccination (mean of 90 days, rho = 0.5306, p = 0.0003). Thus, the Fujirebio S and Roche S results were very similar, but neither correlated with neutralizing antibody titers by MBL Neu at a later time after vaccination.

Objectives: Interstitial lung disease (ILD) is an extra-articular manifestation in rheumatoid arthritis (RA), detected in 10.7% of patients, and causing a poor prognosis. Hence, biomarkers for ILD are urgently required in RA. Low molecular weight metabolites can be assessed by metabolomic analyses, and although these have been conducted in RA and in idiopathic pulmonary fibrosis, few have been carried out for ILD in the context of RA. Therefore, we analyzed serum metabolomic profiles of ILD in RA to identify novel biomarkers.Methods: Serum samples from 100 RA patients with ILD and 100 matched RA patients without chronic lung disease (CLD) were collected. These samples were subjected to metabolomic analyses using capillary electrophoresis time-of-flight mass spectrometry.Results: A total of 299 metabolites were detected in the metabolomic analysis. By univariate analysis, serum levels of decanoic acid and morpholine were lower in RA with ILD (false discovery rate Q = 1.87 × 10−11 and 7.09 × 10−6, respectively), and glycerol was higher (Q = 1.20 × 10−6), relative to RA without CLD. Serum levels of these metabolites in RA with usual interstitial pneumonia or RA with non-specific interstitial pneumonia were also altered. The partial least squares-discriminant analysis model generated from these three metabolites could successfully discriminate ILD in RA (area under the curve: 0.919, 95% confidence interval: 0.867–0.968, sensitivity 0.880, specificity 0.780).Conclusions: Serum levels of some metabolites were significantly different in RA with ILD compared with RA without CLD. It is concluded that metabolomic profiling will be useful for discovering candidate screening biomarkers for ILD in RA.

Background:. Burn injury is one of the most debilitating traumas, which induces multiple organ dysfunctions, resulting in high levels of morbidity and mortality. Fibroblast growth factor 2 (FGF2) has been applied to burn injury, whose precise mechanisms underlying facilitating the healing have not been fully understood. Although various animal models have been developed in pigs, rabbits, rats, and mice, no mouse model that creates burns consistent in their extent and depth have not been developed. Here, we developed a mouse burn model, and investigated details of the burn process, and elucidated the mechanisms of FGF2 effects. Methods:. A device with an 8-mm metal probe and a temperature controller was developed, which controls the temperature of the probe. Using the device, 1 or 2 of full-thickness burn injuries were generated on the back under catagen/telogen of 6-month-old C57BL/6 male mice. After 24 hours, FGF2 or phosphate-buffered saline was injected into the injured region, and at days 3, 5, and 7, histological and immunohistochemical analysis was performed to observe the injury and repair process. Results:. The device constantly generated a mouse full-thickness burn injury. The repair was initiated on the bottom of the burn as well as the margin. Local treatment with FGF2 displayed higher levels of immunostaining for both CD31+ and alpha-smooth muscle actin. Conclusions:. The device we developed is useful to generate a mouse burn injury model. FGF2 facilitates tissue repair with an increased number of both CD31+ and αSMA+ cells.