Myeloid-derived suppressor cell-derived osteoclasts with bone resorption capacity in the joints of arthritic SKG mice.

Background: Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells with immunosuppressive functions. It is known that MDSCs are expanded at inflammatory sites after migrating from bone marrow (BM) or spleen (Sp). In chronic inflammatory diseases such as rheumatoid arthritis (RA), previous reports indicate that MDSCs are increased in BM and Sp, but detailed analysis of MDSCs in inflamed joints is very limited. Objective: The purpose of this study is to characterize the MDSCs in the joints of mice with autoimmune arthritis. Methods: We sorted CD11b+Gr1+ cells from joints (Jo), bone marrow (BM) and spleen (Sp) of SKG mice with zymosan (Zym)-induced arthritis and investigated differentially expressed genes (DEGs) by microarray analysis. Based on the identified DEGs, we assessed the suppressive function of CD11b+Gr1+ cells from each organ and their ability to differentiate into osteoclasts. Results: We identified MDSCs as CD11b+Gr1+ cells by flow cytometry and morphological analysis. Microarray analysis revealed that Jo-CD11b+Gr1+ cells had different characteristics compared with BM-CD11b+Gr1+ cells or Sp-CD11b+Gr1+ cells. Microarray and qPCR analysis showed that Jo-CD11b+Gr1+ cells strongly expressed immunosuppressive DEGs (Pdl1, Arg1, Egr2 and Egr3). Jo-CD11b+Gr1+ cells significantly suppressed CD4+ T cell proliferation and differentiation in vitro, which confirmed Jo-CD11b+Gr1+ cells as MDSCs. Microarray analysis also revealed that Jo-MDSCs strongly expressed DEGs of the NF-κB non-canonical pathway (Nfkb2 and Relb), which is relevant for osteoclast differentiation. In fact, Jo-MDSCs differentiated into osteoclasts in vitro and they had bone resorptive function. In addition, intra-articular injection of Jo-MDSCs promoted bone destruction. Conclusions: Jo-MDSCs possess a potential to differentiate into osteoclasts which promote bone resorption in inflamed joints, while they are immunosuppressive in vitro.

Association of large joint involvement at the start of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors with disease activity and drug retention in patients with rheumatoid arthritis: The ANSWER cohort study.

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.

Comparison of retention of biologics in Japanese patients with elderly-onset rheumatoid arthritis-the ANSWER cohort study.

OBJECTIVES: This multicentre, retrospective study aimed to compare retention and reasons for discontinuation between Janus kinase inhibitors (JAKi) and biologic disease-modifying antirheumatic drugs in patients with elderly-onset rheumatoid arthritis (EORA). METHODS: Patients with RA enrolled in a Japanese multicentre observational registry between 2015 and 2022 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding factors by indication for initiation of tumor necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), cytotoxic T-lymphocyte associated antigen 4 immunoglobulin (CTLA4-Ig) blockers, or JAKi, a propensity score based on baseline characteristics was used to compare drug retention. To assess the reasons for discontinuation, retention rates for ineffectiveness, adverse events, and remission were analyzed as secondary outcomes. RESULTS: A total of 572 patients with 835 treatment courses were identified (314 TNFi, 175 IL-6i, 228 CTLA4-Ig, and 118 JAKi). After adjusting for differences in baseline characteristics, drug retention was significantly higher for IL-6i (HR = 0.38, 95%CI = 0.27-0.55, p< 0.01) as compared with TNFi. Discontinuation due to lack of effectiveness was lower with the JAKi (HR = 0.38, 95%CI = 0.22-0.66, p< 0.01) and the IL-6i (HR = 0.29, 95%CI = 0.19-0.46, p< 0.01) as compared with the TNFi although the CTLA4-Ig had a similar HR to TNFi. The adjusted incidence of discontinuation due to adverse event was higher in the JAKi (HR = 2.86, 95%CI = 1.46-5.59, p< 0.01) than the TNFi. CONCLUSIONS: In EORA patients, IL-6i and JAKi had longer retention and less discontinuation due to ineffectiveness than TNFi. The potential risks of JAKi should be approached with an individualized perspective.

Comparative effectiveness of biological disease-modifying antirheumatic drugs and Janus kinase inhibitor monotherapy in rheumatoid arthritis.

OBJECTIVES: To examine the effectiveness and drug tolerability of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitor (JAKi) monotherapy in patients with rheumatoid arthritis (RA) in a multicentre cohort study. METHODS: Patients with RA initiated with bDMARD/JAKi monotherapy without conventional synthetic DMARDs were included. Monotherapy regimens were categorised as interleukin-6 receptor inhibitors (IL-6Ri), cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4Ig), JAKi, or tumour necrosis factor inhibitors (TNFi). Multiple propensity score-based inverse probability weighting (IPW) was used to reduce selection bias. Linear mixed-effect models with IPW were used to examine changes in the disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) at 24 weeks, and drug retention was compared among monotherapy using IPW Cox proportional hazards models. RESULTS: A total of 849 treatment courses from 635 patients were included (IL-6Ri, 218; CTLA4Ig, 183; JAKi, 92; TNFi, 356). The difference in change in DAS28-ESR at week 24 as the primary outcome was -0.93 (95% CI: -1.20 to -0.66) lower in the IL-6Ri group than TNFi, while that of CTLA4Ig and JAKi was similar with that of TNFi (-0.20 [-0.48 to 0.08], -0.25 [-0.67 to 0.16], respectively). IL-6Ri use was associated with significantly lower overall drug discontinuation than TNFi use (hazard ratio = 0.55 [0.39-0.78], P = 0.001). Similar retention rates were identified among CTLA4Ig and JAKi compared to TNFi. CONCLUSION: In the analysis with IPW to reduce selection bias, IL-6Ri monotherapy was superior to TNFi monotherapy in terms of effectiveness and drug retention. No significant differences were identified between CTLA4Ig, JAKi, and TNFi monotherapy.

Real-world comparative study of the efficacy of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study.

OBJECTIVE: This multicentre, retrospective study compared the efficacy and safety of tofacitinib, baricitinib, peficitinib and upadacitinib in real-world clinical settings after minimizing selection bias and adjusting the confounding patient characteristics. METHOD: The 622 patients were selected from the ANSWER cohort database and treated with tofacitinib (TOF), baricitinib (BAR), peficitinib (PEF) or upadacitinib (UPA). The patient's background was matched using propensity score-based inverse probability of treatment weighting (IPTW) among four treatment groups. The values of Clinical Disease Activity Index (CDAI), C-reactive protein (CRP), and modified Health Assessment Questionnaire (mHAQ) after drug initiation and the remission or low disease activity (LDA) rates of CDAI at 6 months after drug initiation were compared among the four groups. Further, the predictive factor for TOF and BAR efficacy was analysed. RESULTS: The retention and discontinuation rates until 6 months after drug initiations were not significantly different among the four JAK inhibitors treatment groups. Mean CDAI value, CDAI remission rate, and CDAI-LDA rate at 6 months after drug initiation were not significantly different among treatment groups. Baseline CDAI (TOFA: OR 1.09, P < 0.001; BARI: OR 1.07, P < 0.001), baseline CRP (TOFA: OR 1.32, P = 0.049), baseline glucocorticoid dose (BARI: OR 1.18, 95% CI 1.01-1.38, P = 0.035), a number of previous biological or targeted synthetic disease-modifying antirheumatic drugs (biological/targeted synthetic DMARDs) (BARI: OR 1.36, P = 0.004) were predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. CONCLUSION: The efficacy and safety of TOF, BAR, PEF and UPA were not significantly different for the treatment of patients with rheumatoid arthritis.

Trends of disease activity in Japanese patients over 75 years with rheumatoid arthritis from 2014 to 2021- the ANSWER cohort study.

OBJECTIVES: To investigate if disease activity among elderly RA patients over 75 years has changed over time in the real-world clinical setting. METHODS: Data from an observational multicentre registry of RA patients in Japan were analyzed. The primary outcome was to evaluate the changes in the proportion of very elderly RA patients (over 75 years) who achieved remission and low disease activity, from 2014 to 2021. The secondary outcome was to identify factors associated with remission and low disease activity by comparing demographic and clinical characteristics among the patients who had a study visit within the study period, using multivariate logistic regression. RESULTS: A total of 32 161 patient visits were identified from 2014 to 2021. The proportion of patients over 75 years increased from 16.5% to 26.9%, with biologics and targeted-synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) usage increasing and glucocorticoids usage decreasing, while conventional-synthetic DMARDs usage remained relatively stable. The proportion of RA patients over 75 years achieving remission and low disease activity significantly increased from 62.2% to 78.2% (p for trend < 0.001). A negative factor associated with achieving remission and low disease activity was glucocorticoid usage, seropositivity, and history of previous b/tsDMARDs use while MTX usage was associated positively, independent of other predictors. CONCLUSIONS: In our cohort, disease activity among very elderly RA patients has improved over time. The study suggests the importance of using a treat-to-target approach in very elderly RA patients to improve clinical outcomes.

Association of anti-ß2-glycoprotein I/HLA-DR complex antibody with arterial thrombosis in female patients with systemic rheumatic diseases.

BACKGROUND: ß2-glycoprotein I (ß2GPI) complexed with human leukocyte antigen DR (ß2GPI/HLA-DR) was found to be a major autoantibody target in antiphospholipid syndrome (APS). This study aimed to reveal the association between anti-ß2GPI/HLA-DR antibodies and vascular thromboses in women with systemic rheumatic diseases. METHODS: We conducted a retrospective longitudinal study. We measured anti-ß2GPI/HLA-DR antibodies and compared them with anti-phospholipid antibody (aPL) profiles and the adjusted global antiphospholipid syndrome score (aGAPSS). Using receiver operating characteristic (ROC) analysis, we determined the best cut-off value for arterial thrombosis. We also evaluated the validity of anti-ß2GPI/HLA-DR antibodies by adding to conventional cardiovascular risk factors in multivariate logistic analysis. RESULTS: We evaluated 704 patients, including 66 (obstetric or thrombotic) APS, 13 primary APS, and 78 asymptomatic aPL carriers. Seventy-seven patients had a history of arterial thrombosis, and 14 patients had both arterial and venous thrombosis. These 14 patients, as well as patients with aGAPSS > 10 or triple-positive aPL profiles, displayed high anti-ß2GPI/HLA-DR antibody titers. The ROC curve showed a sensitivity, specificity, and area under the curve (AUC) for arterial thrombosis of 33.8%, 91.4%, and 0.6009, respectively, with a cut-off value of 172.359 U/mL. The anti-ß2GPI/HLA-DR antibody positivity using this cut-off value yielded an odds ratio of 5.13 (95%CI: 2.85-9.24), significantly improving the AUC from 0.677 to 0.730. CONCLUSION: Anti-ß2GPI/HLA-DR antibodies are associated with arterial thrombosis in female patients with systemic rheumatic diseases.

Demographic, Physical, and Psychological Determinants of Patient Experience with Subcutaneous Self-Injection in Patients with Rheumatoid Arthritis: Structural Equation Modeling Approach.

Purpose: To achieve a better patient experience with self-injection, an assessment of potential demographic, physical, and psychological barriers is necessary. The aim of this study was to examine the demographic, physical, and psychological characteristics associated with the experiences of self-injection in patients with rheumatoid arthritis (RA). Patients and Methods: In this study, overall patient experience with subcutaneous self-injection was assessed using the Self-Injection Assessment Questionnaire. Upper limb function was assessed using the three domains of the Health Assessment Questionnaire associated with upper extremity disability (dressing and grooming, eating, and grip). Structural equation modeling was used to estimate the association between the demographic and clinical characteristics of patients with RA and their experiences with self-injection in the theoretical model. Results: Data from 83 patients with RA were analyzed. Compared with younger patients, elderly patients were more likely to experience lower self-confidence, self-image, and ease of use. Female patients had lower ease of use than male patients. In terms of upper limb function, patients with more difficulty in performing activities of daily living were more likely to have a lower self-image. Self-injection perceptions before learning the method of injection, such as fear of needles and anxiety about self-injection, were associated with post-injection feelings, injection site reactions, self-confidence, and ease of use. Conclusion: To optimize patients' experiences with self-injection, healthcare workers should assess each patient's age, sex, upper limb function, and pre-self-injection perceptions as demographic, physical, and psychological barriers.

Instability of harmonized thyroid-stimulating hormone immunoassays in clinical practice.

OBJECTIVE: Thyroid-stimulating hormone (TSH) harmonization is effective in minimizing differences between the results of immunoassays in healthy subjects. However, the effectiveness of TSH harmonization in clinical practice has not been investigated. The aim of this study was to evaluate the instability of TSH harmonization in clinical practice. METHODS: We compared the reactivities of four harmonized TSH immunoassays using combined difference plots of 431 patients. We selected patients with statistically significant deviations in TSH levels and analyzed their thyroid hormone levels and clinical characteristics. RESULTS: The combined difference plots showed that one harmonized TSH immunoassay exhibited markedly different reactivity even after TSH harmonization compared with the other three immunoassays. Among 109 patients with mild-to-moderate elevation of TSH levels, we selected 15 patients with statistically significant deviations in TSH levels according to the difference plots of three harmonized TSH immunoassays, excluding one immunoassay that showed different reactivity. The thyroid hormone levels of three patients were misclassified as hypothyroidism or normal due to deviating TSH levels. In terms of clinical characteristics, these patients were in poor nutritional status and general condition, possibly due to their severe illness (e.g., advanced metastatic cancer). CONCLUSION: We have confirmed that TSH harmonization in clinical practice is relatively stable. However, some patients showed deviating TSH levels in the harmonized TSH immunoassays, indicating the need for caution, particularly in poorly nourished patients. This finding suggests the presence of factors that contribute to the instability of TSH harmonization in such cases. Further investigation is warranted to validate these results.

Exosomes derived from synovial fibroblasts from patients with rheumatoid arthritis promote macrophage migration that can be suppressed by miR-124-3p.

Objectives: Exosomes are potent vehicles for intercellular communication. Rheumatoid arthritis (RA) is a chronic systemic disease of unknown etiology. Local administration of miR-124 precursor to rats with adjuvant-induced arthritis suppresses systemic arthritis and bone destruction. Thus, exosomes may be involved in this disease. We aimed to determine the role of exosomes in the pathology of RA. Methods: Fibroblast-like synoviocytes (FLS) were collected from patients with RA and osteoarthritis (OA). miR-124-3p mimic was transfected into the RA FLS (RA miR-124 FLS). Exosomes were collected from the culture medium by ultracentrifugation. Macrophages were produced from THP-1 cells. MicroRNAs in the exosomes were analyzed using real-time PCR. Proteomics analysis was performed using nanoscale liquid chromatography-tandem mass spectrometry. Macrophage migration was evaluated using a Transwell migration assay. SiRNA was used to knockdown proteins of interest. Results: MicroRNAs in the RA FLS, RA miR-124 FLS, and OA FLS exosomes were similar. Proteomics analysis revealed that pentraxin 3 (PTX3) levels were higher in RA FLS exosomes than in RA miR-124 FLS and OA FLS exosomes, and proteasome 20S subunit beta 5 (PSMB5) levels were lower in RA FLS exosomes than in RA miR-124 FLS and OA FLS exosomes. The RA FLS exosomes promoted and the RA miR-124 FLS exosomes suppressed macrophage migration. PTX3-silenced RA FLS exosomes suppressed and PSMB5-silenced OA FLS exosomes promoted macrophage migration. Conclusions: RA FLS exosomes promote macrophage migration via PTX3 and PSMB5, and miR-124-3p suppresses this migration.

Association of Neonatal Serum Creatinine Concentration with Maternal Serum Creatinine Concentration and Birth Weight.

BACKGROUND: The serum creatinine (SCr) concentration in neonates is generally high for its body size, compared to those of infants. The aim of the present study was to investigate the effect of maternal SCr on neonatal SCr through measurements of prenatal maternal SCr and neonatal SCr from birth to postnatal Day 5. In addition, postnatal changes in SCr were compared between term and preterm infants, given that few studies have addressed this topic. METHODS: The retrospective study subjects were 151 neonates whose Scr was measured consecutively from birth to postnatal Day 5 and 124 mothers whose SCr was measured prenatally. RESULTS: There were significant correlations between maternal SCr and neonatal SCr at birth (r = 0.858, p < 0.001) and on postnatal Day 1 (r = 0.235, p < 0. 001). The SCr of term infants (median 0.69 mg/dL, range 0.54 - 0.96 mg/ dL) were higher than those of preterm infants (median 0.63 mg/dL, range 0.43 - 1.23 mg/dL, p < 0.001) at birth; however, these values were reversed on postnatal Day 1 (Term: median 0.75 mg/dL, range 0.51 - 1.13 mg/dL, Pre-term: median 0.88 mg/dL, range 0.56 - 1.25 mg/dL, p < 0.001). There were differences in the timing of reaching to peak SCr between preterm and term neonates. In addition, birth weight might affect SCr concentrations after birth. CONCLUSIONS: The results of this study suggest that neonatal SCr is influenced by maternal SCr, although the effect disappears by postnatal Day 2. Moreover, glomerular filtration rate differs between term and preterm infants.

Severe Lupus Myocarditis Preceded by Mesalazine-induced Lupus.

In drug-induced lupus (DIL), symptoms similar to those of systemic lupus erythematosus (SLE) usually resolve after discontinuation of the offending drug. A 41-year-old-woman with a history of ulcerative colitis presented with polyarthritis and myositis and was positive for anti-double stranded (ds) DNA IgG antibody. After discontinuation of mesalazine, the symptoms resolved, and the antibody titer decreased. The patient was diagnosed with DIL. Six months later, lupus myocarditis developed. After treatment with glucocorticoids, cyclophosphamide, intravenous immunoglobulin, and an intra-aortic balloon pump, she showed dramatic improvement. Patients with DIL and an immunological predisposition, such as anti-dsDNA antibodies, may have SLE and should be carefully monitored.

Comparison of 17 serological treponemal and nontreponemal assays for syphilis: A retrospective cohort study.

Objectives: Rapid plasma reagin (RPR) and Treponema pallidum (TP) antibody test kits are often used to diagnose syphilis, although the relationship between their measured values is unclear. We aimed to reveal the relevance of these kits' results. Design and methods: In all, 143 sera from 110 patients were tested using 12 TP kits and 5 RPR kits and the results compared. Results: The specificity and sensitivity of RPR kits were 81-96% and 95-100%, respectively. The correlation coefficients (0.849-0.934) considerably differed between the manual RPR card test and latex agglutination (LA) assay kits. The following sensitivities were obtained: 82-91% for TP fluorescent treponemal antibody absorption assay (FTA-ABS), TP hemagglutination assay (HA), and TP particle agglutination assay (PA); 94-95% for TP LAs; and 92-100% for chemiluminescent immunoassay (CLIA), chemiluminescent enzyme immunoassay (CLEIA), and immunochromatography assay (IC). Correlation coefficients between TP kits were 0.753-0.974, and the measured values varied. Changes in RPR and quantifiable TP kits were the same for patients with reinfected syphilis and with syphilis under treatment. Conclusions: RPR tests had lower specificity than TP antibody tests. RPR card test and RPR LAs had similar specificity and sensitivity, but their measured values were different. RPR should be measured using automatic RPR LA without setting the upper limit of the reported value. RPR LA should also be standardized. The sensitivity of TP antibody was better in CLIA, CLEIA, and IC than in FTA-ABS, HA, PA, and LA. Therefore, TP antibody kits should be standardized and quantified.

Large-scale serosurveillance of COVID-19 in Japan: Acquisition of neutralizing antibodies for Delta but not for Omicron and requirement of booster vaccination to overcome the Omicron's outbreak.

Continuous appearance of SARS-CoV-2 variants and mass vaccination have been intricately influencing on the COVID-19 situation. To elucidate the current status in Japan, we analyzed totally 2,000 sera in August (n = 1,000) and December (n = 1,000) 2021 collected from individuals who underwent a health check-up. The anti-N seropositive rate were 2.1% and 3.9% in August and December 2021, respectively, demonstrating a Delta variant endemic during that time; it was approximately twofold higher than the rate based on the PCR-based diagnosis. The anti-S seropositive rate was 38.7% in August and it reached 90.8% in December, in concordance with the vaccination rate in Japan. In the December cohort, 78.7% of the sera showed neutralizing activity against the Delta variant, whereas that against the Omicron was much lower at 36.6%. These analyses revealed that effective immunity against the Delta variant was established in December 2021, however, prompt three-dose vaccination is needed to overcome Omicron's outbreak.

Genetic Analysis of UGT1A1 Polymorphisms Using Preserved Dried Umbilical Cord for Assessing the Potential of Neonatal Jaundice as a Risk Factor for Autism Spectrum Disorder in Children.

Neonatal jaundice has been suggested as a perinatal risk factor for autism spectrum disorder (ASD). We examined UGT1A1 polymorphisms to assess the potential of neonatal jaundice as a risk factor for ASD in children by using DNA extracted from preserved umbilical cord. In total, 79 children with ASD were genotyped for UGT1A1*28 (c.-41-40dup), UGT1A1*6 (c.211 G > A), and UGT1A1*27 (c.686 C > A). The allele frequency of UGT1A1*6 (OR = 1.34, p = 0.26) and UGT1A1*28 (OR = 0.80, p = 0.54) and the prevalence of UGT1A1*28/*6 diplotypes did not differ significantly from those in the control population. No UGT1A1*27 allele was detected in the subjects. ASD symptom assessment scores were not associated with UGT1A1*28/*6/*27 genotypes or UGT1A1*28/*6 diplotypes. These results suggest that neonatal jaundice is not significantly associated with ASD.

Comparative effectiveness of trimethoprim-sulfamethoxazole versus atovaquone for the prophylaxis of pneumocystis pneumonia in patients with connective tissue diseases receiving prolonged high-dose glucocorticoids.

We compared the prophylactic effect of trimethoprim-sulfamethoxazole (TMP-SMX) with atovaquone for pneumocystis pneumonia (PCP) in patients with connective tissue diseases (CTDs) receiving high-dose glucocorticoids. Patients with CTDs aged ≥ 18 years who were treated with a prolonged course (≥ 4 weeks) of glucocorticoids (≥ 20 mg/day prednisone) in a Japanese tertiary center between 2013 and 2017 were included. The patients were categorized into two groups: TMP-SMX and atovaquone group. Adjusted cumulative incidence of PCP was compared between the two groups after propensity score weighting for differences in confounding factors. A total of 480 patients with a prolonged high-dose glucocorticoid treatment were identified. Out of 383 patients with TMP-SMX prophylaxis, 102 (26.8%) patients experienced adverse events leading to discontinuation within 4 weeks of initiation, while no patient in the atovaquone discontinued the therapy. Two hundred eighty-one patients received TMP-SMX, while 107 received atovaquone for PCP prophylaxis. During a total of 397.0 person-years, 7 PCP cases (2 in the TMP-SMX, 5 in the atovaquone) occurred with a mortality rate of 54.5%. After adjusting for differences in baseline characteristics, the adjusted cumulative incidence of PCP was similar between the two group (HR 0.97, 95% CI 0.19-5.09, p = 0.97). Prophylactic effects for PCP in CTDs patients receiving prolonged high-dose glucocorticoids were similar between TMP-SMX and atovaquone. Atovaquone was well-tolerated with no side effects.

Identification of plexin D1 on circulating extracellular vesicles as a potential biomarker of polymyositis and dermatomyositis.

OBJECTIVES: We aimed to identify disease-specific surface proteins on extracellular vesicles (EVs) as novel serum biomarkers of PM/DM. METHODS: We performed liquid chromatography-tandem mass spectrometry (LC/MS) on purified EVs from sera of 10 PM/DM patients, 23 patients with other autoimmune diseases and 10 healthy controls (HCs). We identified membrane proteins preferentially present in EVs of PM/DM patients by bioinformatics and biostatistical analyses. We developed an EV sandwich ELISA for directly detecting serum EVs expressing disease-specific membrane proteins and evaluated their clinical utility using sera from 54 PM/DM, 24 RA, 20 SLE, 13 SSc and 25 Duchenne and Becker types of muscular dystrophy (DMD/BMD) patients and 36 HCs. RESULTS: LC/MS analysis identified 1220 proteins in serum EVs. Of these, plexin D1 was enriched in those from PM/DM patients relative to HCs or patients without PM/DM. Using a specific EV sandwich ELISA, we found that levels of plexin D1+ EVs in serum were significantly greater in PM/DM patients than in HCs or RA, SLE or DMD/BMD patients. Serum levels of plexin D1+ EVs were greater in those PM/DM patients with muscle pain or weakness. Serum levels of plexin D1+ EVs were significantly correlated with levels of aldolase (rs = 0.481), white blood cells (rs = 0.381), neutrophils (rs = 0.450) and platelets (rs = 0.408) in PM/DM patients. Finally, serum levels of plexin D1+ EVs decreased significantly in patients with PM/DM in clinical remission after treatment. CONCLUSION: We identified levels of circulating plexin D1+ EVs as a novel serum biomarker for PM/DM.

Serum Cytokine Profiles of Rapid Recovery Patients with COVID-19: Series of 6 Cases.

COVID-19 patients reveal various clinical manifestations; however, the specific mechanisms and factors contributing to rapid recovery remain unclear. We performed serum cytokine profiling using a bead-based immunoassay in six COVID-19 patients with mild symptoms who experienced rapid recovery. All patients had fever that resolved within 4 days. During the study, the interferon gamma-related protein 10 (IP-10) level rapidly increased initially, and then rapidly decreased in all six patients. Similarly, the interferon (IFN)-λ 2/3 levels rapidly increased initially, and then decreased in five of the six patients. IP-10 and IFN-λ2/3 may play a key role in the rapid recovery of mild COVID-19.

Massive surge of mRNA expression of clonal B-cell receptor in patients with COVID-19.

BACKGROUND: Antibody production is one of the primary mechanisms for recovery from coronavirus disease 2019 (COVID-19). It is speculated that massive clonal expansion of B cells, which can produce clinically meaningful neutralizing antibodies, occurs in patients who recover on the timing of acquiring adaptive immunity. METHODS: To evaluate fluctuations in clonal B cells and the size of the clones, we chronologically assessed the B-cell receptor (BCR) repertoire in three patients with COVID-19 who recovered around 10 days after symptom onset. RESULTS: We focused on the three dominant clonotypes (top 3) in each individual. The percentage frequencies of the top 3 clonotypes increased rapidly and accounted for 27.8 % on day 9 in patient 1, 10.4 % on day 12 in patient 2, and 10.8 % on day 11 in patient 3, respectively. The frequencies of these top 3 clonotypes rapidly decreased as the patients' clinical symptoms improved. Furthermore, BCR network analysis revealed that accumulation of clusters composed of similar complementarity-determining region 3 (CDR3) sequences were rapidly formed, grew, and reached their maximum size around 10 days after symptom onset. CONCLUSIONS: BCR repertoire analysis revealed that a massive surge of some unique BCRs occurs during the acquisition of adaptive immunity and recovery. The peaks were more prominent than expected. These results provide insight into the important role of BCRs in the recovery from COVID-19 and raise the possibility of developing neutralizing antibodies as COVID-19 immunotherapy.