TGF-ß3 in differentiation and function of Tph-like cells and its relevance to disease activity in patients with systemic lupus erythematosus.

OBJECTIVES: T peripheral helper (Tph) cells have major roles in pathological processes in SLE. We sought to clarify the mechanisms of Tph cell differentiation and their relevance to clinical features in patients with SLE. METHOD: Phenotypes and functions of Tph cell-related markers in human CD4+ T cells purified from volunteers or patients were analysed using flow cytometry and quantitative PCR. Renal biopsy specimens from patients with LN were probed by multicolour immunofluorescence staining. RESULTS: Among multiple cytokines, transforming growth factor (TGF)-ß3 characteristically induced programmed cell death protein 1 (PD-1)hi musculoaponeurotic fibrosarcoma (MAF)+, IL-21+IL-10+ Tph-like cells with a marked upregulation of related genes including PDCD-1, MAF, SOX4 and CXCL13. The induction of Tph-like cells by TGF-ß3 was suppressed by the neutralization of TGF-ß type II receptor (TGF-ßR2). TGF-ß3-induced Tph-like cells efficiently promoted the differentiation of class-switch memory B cells into plasmocytes, resulting in enhanced antibody production. The proportion of Tph cells in the peripheral blood was significantly increased in patients with SLE than in healthy volunteers in concordance with disease activity and severity of organ manifestations such as LN. TGF-ß3 was strongly expressed on macrophages, which was associated with the accumulation of CD4+ C-X-C chemokine receptor (CXCR5)-PD-1+ Tph cells, in the renal tissue of patients with active LN. CONCLUSION: The induction of Tph-like cells by TGF-ß3 mainly produced from tissue macrophages plays a pivotal role in the pathological processes of active LN by enhancing B-cell differentiation in patients with SLE.

Biological/targeted synthetic DMARDs do not arrest bone loss in patients with rheumatoid arthritis: a multicenter prospective observational study.

OBJECTIVE: To elucidate the differential effects of biological/target synthesized DMARDs (b/tsDMARDs) on bone metabolism in patients with rheumatoid arthritis (RA) in a real-world cohort. METHODS: This was a multicentre prospective observational study of RA patients enrolled at the time of 1st b/tsDMARDs administration. Bone mineral density (BMD) and bone turnover markers (BTMs) were measured during the 52-week observation. The study was designed to enrol all eligible RA patients. The end-points were differences in changes in BMD according to b/tsDMARD type, and the correlation between BMD and BTMs. RESULTS: A total of 1,164 patients were enrolled in this study. b/tsDMARDs improved RA disease activity from mean CDAI 25.5 at baseline to 4.5 at week 26. Patients not receiving anti-osteoporotic agents (anti-OP) at baseline with no history of fracture experienced a significant decrease in both femoral neck (F: mean 0.666-0.655 g/cm3) and radial (R: 0.518-0.514) BMD at week 26. Despite maintaining low CDAI levels during weeks 26-52 (5.3-4.4), there was a continued decline in BMD (F: 0.653, R: 0.509. Weeks 52). None of b/tsDMARDs type preserved BMD. Conversely, patients receiving anti-OP at baseline maintained stable BMD throughout the study (Weeks 0/26/52. F: 0.551/0.551/0.555, R: 0.415/0.416/0.415). Although BTMs were changed by b/tsDMARDs, the changes were unrelated to those in BMD. CONCLUSION: Our study suggested the progression of osteoporosis in RA patients during b/tsDMARDs treatment without anti-OP. BTMs may not reflect BMD change. Regular monitoring of BMD in RA should be considered for early management of osteoporosis.

Usefulness of ultrasound as a predictor of elderly-onset rheumatoid arthritis with polymyalgia rheumatica-like onset.

OBJECTIVES: Differentiation between polymyalgia rheumatica (PMR) and elderly-onset rheumatoid arthritis (EORA), especially in elderly patients, is often difficult due to similarities in symptoms and serological kinetics. In this study, we aimed to analyse the predictors of EORA with PMR-like onset. METHODS: Seventy-two patients diagnosed with PMR, who attended our hospital for routine care and underwent musculoskeletal ultrasonography at that time were evaluated. Synovitis was evaluated semi-quantitatively (0-3) by grey scale (GS) and power Doppler (PD) in 24 joints [both hands (wrist, metacarpophalageal, and proximal interphalangeal joints) and both shoulder joints]. RESULTS: Overall, 18 patients had rheumatoid arthritis (25.0%); the mean age was 75.0 years, and 34.7% and 65.3% were male and female, respectively. In PMR and PMR/EORA groups, multivariate logistic analysis showed that rheumatoid factor positivity, GS ≥2 of hand joints, and PD ≥1 of hand joints were independent factors with significant differences. At least one of the three factors had a sensitivity of 88.9% and specificity of 92.6%. CONCLUSIONS: The presence of at least one of the criteria: rheumatoid factor positivity, GS ≥ 2, and PD ≥ 1 of hand joints, suggested the possibility of developing EORA within 1 year of PMR diagnosis.

An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus.

OBJECTIVE: To evaluate the dysfunction of B-cell metabolism and its involvement in SLE pathology. METHODS: We assessed the expression of metabolic markers of B cells in the peripheral blood of healthy controls (HCs) and SLE patients by using flow cytometry. In vitro, peripheral B cells were isolated from HCs and SLE patients to investigate the metabolic regulation mechanisms involved in their differentiation. RESULTS: The expression level of DiOc6 (mitochondrial membrane hyperpolarization) was higher in B cells from SLE patients than in HCs, and correlated to the percentage of plasmablasts in CD19+ cells and with SLEDAI, a disease activity score. Stimulation of CD19+ cells with the Toll-like receptor 9 (TLR9) ligand CpG and IFN-α enhanced glycolysis, oxidative phosphorylation (OXPHOS), DiOc6 expression, and plasmablast differentiation in vitro. In the absence of glutamine, both glycolysis and OXPHOS were reduced, and plasmablast differentiation was suppressed, whereas there was no change in the absence of glucose. As glutamine is an important nutrient for protein synthesis, we further investigated the effect of the glutaminase inhibitor BPTES, which inhibits glutamine degradation, on metabolic regulation. BPTES reduced DiOc6 expression, OXPHOS, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) production, plasmablast differentiation without affecting glycolysis. Metformin inhibited CpG- and IFN-α-induced glutamine uptake, mitochondrial functions and suppressed plasmablast differentiation. CONCLUSIONS: Mitochondrial dysfunction in B cells is associated with plasmablast differentiation and disease activity in SLE. Enhanced mitochondrial functions mediated by glutamine metabolism are important for plasmablast differentiation, which may be a potential therapeutic target for SLE.

mTOR activation in CD8+ cells contributes to disease activity of rheumatoid arthritis and increases therapeutic response to TNF inhibitors.

OBJECTIVE: This study aimed to understand the role of mammalian target of rapamycin (mTOR) in CD8+ cells in the pathogenicity of RA and the changes after treatment with biologic drugs. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 17 healthy controls and 86 patients with RA. Phosphorylation of mTOR (p-mTOR) and its clinical relevance were evaluated. The role of mTOR in CD8+ cells was also examined in vitro. RESULTS: Patients with RA who had a moderate or high disease activity, were biologic-naïve, and were refractory to MTX were enrolled in this study. The p-mTOR levels in CD8+ cells were higher in patients with RA than in healthy controls, and they positively correlated with the disease activity in such patients. However, after one year of treatment with TNF inhibitors, the p-mTOR levels in CD8+ cells were suppressed and showed a positive correlation with the treatment response, which was not observed in the abatacept-treatment group. In vitro stimulation of CD8+ cells with anti-CD3 and anti-CD28 antibodies induced mTOR phosphorylation and increased the production of granzyme B, granulysin, TNF-α and IFN-γ but decreased the production of granzyme K. However, on treatment with TNF inhibitors, p-mTOR levels in CD8+ cells and granzyme B production decreased, while granzyme K production increased. The production of granulysin and IFN-γ was not affected by the TNF inhibitors. CONCLUSION: These results suggested that mTOR activation in CD8+ cells may be a novel evaluation marker for RA disease activity and a predictive marker of therapeutic response to TNF inhibitors.

Pathological role of activated mTOR in CXCR3+ memory B cells of rheumatoid arthritis.

OBJECTIVES: B cells play an important pathological role in RA. In this study, we investigated the role of metabolic regulator mTOR in B cells and its relevance to the pathology of RA. METHODS: Peripheral blood mononuclear cells were isolated from 31 normal subjects and 86 RA patients and the gated B cells were assessed for mTOR phosphorylation and chemokine receptor expression. In vitro studies on peripheral blood B cells isolated from the control and RA patients investigated the molecular mechanisms. RESULTS: Higher concentrations of CXCL10 (CXCR3 ligands) and lower percentages of CXCR3+ memory B cells were present in the peripheral blood of RA patients relative to the control. RA patients with high CXCL10 concentrations had smaller percentage of CXCR3+ memory B cells and high disease activity. One-year treatment with TNF inhibitors increased the percentage of CXCR3+ memory B cells and reduced serum CXCL10 concentrations. mTOR phosphorylation in B cells was further enhanced in RA patients, compared with the control, and was selectively enhanced in CXCR3+ memory B cells. mTOR phosphorylation in CXCR3+ memory B cells correlated with disease activity. In vitro, mTOR phosphorylation in B cells enhanced IL-6 production and increased RANKL expression. CONCLUSION: mTOR activation in CXCR3+ memory B cells of RA patients is associated with disease activity, mediated through IL-6 production and RANKL expression. The obtained results also suggest that TNF inhibitors mediate an impact on the association between CXCL10 and mTOR activated CXCR3+ memory B cells.

Severe pulmonary arterial hypertension and interstitial pneumonia related to systemic lupus erythematosus successfully treated with mycophenolate mofetil: A novel case report.

BACKGROUND: Pulmonary arterial hypertension (PAH) and interstitial pneumonia (IP) are relatively rare complications of systemic lupus erythematosus (SLE) and are associated with a poor prognosis. Overcoming these complications is a challenge for improving the prognosis. CASE REPORT: A 41-year-old woman was diagnosed with SLE complicated by IP at the age of 21 years and with antiphospholipid syndrome at the age of 32 years at another hospital. She had been administered prednisolone (PSL) at a dose ≥15 mg daily, as well as various immunosuppressants and antiplatelet/anticoagulation therapy. On day I of hospitalization, She presented to our emergency outpatient department with fever, marked dyspnea, and skin ulcer on the left lower leg and was admitted the same day. Chest radiography revealed marked cardiomegaly and interstitial shadow, and right heart catheterization showed elevation in the mean pulmonary arterial pressure to 47 mmHg, indicating PAH. While oxygen therapy was started, high-dose steroid therapy and mycophenolate mofetil (MMF) were administered for treatment of SLE complicated by PAH/IP, and prostacyclin (prostaglandin I2), endothelin receptor antagonist, and PDE5 inhibitor were administered for PAH. Both SLE disease activity and PAH/IP improved and were maintained with no exacerbation for 2 years. The PSL dose could eventually be reduced to 5 mg/day. CONCLUSION: In SLE complicated by PAH/IP, reports on the efficacy of MMF are scarce, and our findings suggested that MMF may be a treatment option in such cases.

A Machine Learning Approach for Prediction of CDAI Remission with TNF Inhibitors: A Concept of Precision Medicine from the FIRST Registry.

INTRODUCTION: This study aimed to develop low-cost models using machine learning approaches predicting the achievement of Clinical Disease Activity Index (CDAI) remission 6 months after initiation of tumor necrosis factor inhibitors (TNFi) as primary biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) for rheumatoid arthritis (RA). METHODS: Data of patients with RA initiating TNFi as first b/tsDMARD after unsuccessful methotrexate treatment were collected from the FIRST registry (August 2003 to October 2022). Baseline characteristics and 6-month CDAI were collected. The analysis used various machine learning approaches including logistic regression with stepwise variable selection, decision tree, support vector machine, and lasso logistic regression (Lasso), with 48 factors accessible in routine clinical practice for the prediction model. Robustness was ensured by k-fold cross validation. RESULTS: Among the approaches tested, Lasso showed the advantages in predicting CDAI remission: with a mean area under the curve 0.704, sensitivity 61.7%, and specificity 69.9%. Predicted TNFi responders achieved CDAI remission at an average rate of 53.2%, while only 26.4% of predicted TNFi non-responders achieved remission. Encouragingly, the models generated relied solely on patient-reported outcomes and quantitative parameters, excluding subjective physician input. CONCLUSIONS: While external cohort validation is warranted for broader applicability, this study highlights the potential for a low-cost predictive model to predict CDAI remission following TNFi treatment. The approach of the study using only baseline data and 6-month CDAI measures, suggests the feasibility of establishing regional cohorts to generate low-cost models tailored to specific regions or institutions. This may facilitate the application of regional/in-house precision medicine strategies in RA management.

This study aims to enhance the management of rheumatoid arthritis by predicting the likelihood of achieving the treatment target­Clinical Disease Activity Index remission within 6 months of initiating tumor necrosis factor inhibitors. In rheumatoid arthritis, the goal is often Clinical Disease Activity Index remission, and the standard approach involves using medications like methotrexate and biologic/targeted synthetic disease-modifying antirheumatic drugs. However, not all patients respond to these treatments, leading to a trial-and-error process of changing medications. Tumor necrosis factor inhibitors are commonly used as the initial biologic/targeted synthetic disease-modifying antirheumatic drugs for patients who do not respond adequately to methotrexate; however, tumor necrosis factor inhibitor treatment may not achieve effective outcomes for all patients. The study, using a cohort of patients with rheumatoid arthritis treated with tumor necrosis factor inhibitor, has developed a model predicting Clinical Disease Activity Index remission with tumor necrosis factor inhibitors. The models use only standard clinical parameters, therefore no special examination or additional cost is required for the predictions. This approach holds the potential to improve rheumatoid arthritis management by reducing the need for trial-and-error approaches and facilitating more personalized and effective treatment strategies. While further validation is necessary, the study also suggests that creating cost-effective models tailored to specific regions or institutions is possible.

Generation-Dependent Retention Rates and Reasons for Discontinuation of Molecular Targeted Therapies in Patients with Rheumatoid Arthritis: From FIRST Registry.

INTRODUCTION: The study aimed to optimize medical care for elderly patients with rheumatoid arthritis (RA) by examining the 3-year continuation rate of different molecular targeted therapies across age groups in Japan, which has a significant elderly population. METHODS: The study included patients with RA who started molecular targeted therapies between 2013 and 2019 and divided them into three age groups. The primary outcome was to assess the 3-year continuation rate of each drug and analyze reasons for treatment discontinuation using inverse probability of treatment weighting. RESULTS: Among 2292 patients analyzed, tumor necrosis factor (TNF) inhibitors were most commonly used in those younger than 65 years of age (43.5%), while Janus kinase (JAK) inhibitors were also utilized (17.1%). In contrast, JAK inhibitors were less frequently used in patients aged 75 years and older (7.8%), with cytotoxic T lymphocyte antigen 4 immunoglobulin fusion proteins (CTLA4-Ig) being the most common (39.2%). JAK inhibitors and anti-interleukin-6 receptor (IL-6R) antibodies had higher continuation rates than other drugs in patients under 65 years (p < 0.001). For those aged 65-74 years, JAK inhibitors and CTLA4-Ig had higher continuation rates (p < 0.001), while among those aged 75 years and older, CTLA4-Ig and IL-6R antibodies had higher continuation rates (p < 0.001). Inadequate efficacy was the main reason for discontinuation in all age groups, while infection leading to discontinuation increased with age. CONCLUSIONS: The study highlights the need to consider different age groups separately in elderly RA care. Among patients aged 75 years and older, abatacept and anti-IL-6R antibodies showed the highest continuation rates, suggesting their potential suitability and efficacy for this specific age cohort.

Association between ultrasound images and patient-reported outcomes in the treatment of rheumatoid arthritis: a retrospective study.

BACKGROUND: Improvements in the treatment of rheumatoid arthritis (RA) have made it possible to achieve treatment goals. It has been reported that both residual synovitis caused by RA and the patients' subjective symptoms remain even after achieving the treatment goals; however, there are limited reports showing a relationship between them. Furthermore, no studies have evaluated the relationship between patient-reported outcomes (PROs) and subclinical synovitis measured by musculoskeletal ultrasonography (MSUS) in the treatment of RA. This study aimed to investigate residual symptoms and residual synovitis due to remission (REM) or low disease activity (LDA). METHODS: We performed MSUS on 300 patients with RA who attended our hospital for routine care, and we analysed them cross-sectionally by disease activity. Grayscale (GS) and power Doppler (PD) synovitis was evaluated in 22 bilateral hand joints using MSUS. We first performed univariate and multivariate analysis by dividing the data by disease activity. Next, we analysed each PRO in the obtained MSUS results. RESULTS: A multivariate analysis of high disease activity (HDA)/moderate disease activity (MDA) vs. LDA/ REM group identified tender joint count (TJC), pain visual analog scale (VAS) score, and presence or absence of GS score ≥ 2. The one-way analysis of the relationship between the presence or absence of GS score ≥ 2 and each PRO showed a significant difference. In contrast, a multivariate analysis of LDA vs. REM group identified TJC and fatigue VAS score. In REM, PROs alone were relevant, and there was no correlation with MSUS. CONCLUSION: We found that the residual inflammation in the ultrasound images was associated with PROs in the LDA group, but not in the REM group. Trial registration Retrospectively registered.

Short-term effectiveness of ixekizumab to refractory psoriatic arthritis with spondyloarthritis: two case reports.

Psoriatic arthritis (PsA) manifests not only skin lesion but also peripheral and axial joint involvements, thus the disease is considered to be part of spondyloarthritis. In patients with active spondyloarthritis, tumour necrosis factor inhibitors biologics are often considered, but there is not sufficient evidence about other type of biologics. Ixekizumab (IXE) is a humanised monoclonal antibody, which acts against interleukin-17A, a cytokine involved in psoriasis pathogenesis. IXE was administered to two patients with refractory PsA, manifested via extended skin lesions and complicated by axial joint involvement. The effectiveness and imaging results during 12 weeks of treatment were assessed. IXE improved disease activity in both a tumour necrosis factor inhibitors biologics-inadequate responder and a bio-naïve patient and, consequently, IXE probably plays a key role in treatment of axial disease of PsA.

Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells.

Recent reports have shown the importance of IFN-γ and T-bet+ B cells in the pathology of SLE, suggesting the involvement of IFN-γ-producing T-bet+ CD4+ cells, i.e., Th1 cells. This study determined the changes in Th1 subsets with metabolic shift and their potential as therapeutic targets in SLE. Compared with healthy donors, patients with SLE had higher numbers of T-bethiCXCR3lo effector cells and T-bet+Foxp3lo non-suppressive cells, which excessively produce IFN-γ, and lower number of non-IFN-γ-producing T-bet+Foxp3hi activated-Treg cells. These changes were considered to be involved in treatment resistance. The differentiation mechanism of Th1 subsets was investigated in vitro using memory CD4+ cells obtained from healthy donors and patients with SLE. In memory CD4+ cells of healthy donors, both rapamycin and 2-deoxy-D-glucose (2DG) suppressed T-bet+Foxp3- cells, and induced T-bet+Foxp3+(lo/hi) cells. Rapamycin induced IFN-γ-producing T-bet+Foxp3lo cells accompanied with enhanced lipid metabolism, whereas 2DG induced IFN-γ-non-producing T-bet+Foxp3hi cells. In memory CD4+ cells of SLE patients, inhibition of fatty acid synthesis, but not ß-oxidation, suppressed IFN-γ production, and up-regulated of Foxp3 expression in T-bet+Foxp3+ cells. Metabolic regulators such as fatty acid synthesis inhibitors may improve the pathological status by correcting Th1 subset imbalance and overproduction of IFN-γ in SLE.

Fifty-Two-Week Results of Clinical and Imaging Assessments of a Patient with Rheumatoid Arthritis Complicated by Systemic Sclerosis with Interstitial Pneumonia and Type 1 Diabetes despite Multiple Disease-Modifying Antirheumatic Drug Therapy That Was Successfully Treated with Baricitinib: A Novel Case Report.

Baricitinib is a Janus kinase 1/2 (JAK1/2) inhibitor used in the treatment of rheumatoid arthritis. A 71-year-old woman with rheumatoid arthritis complicated by systemic sclerosis and type 1 diabetes that were resistant to multiple disease-modifying antirheumatic drugs started treatment with baricitinib. After baricitinib administration, the disease activity of her rheumatoid arthritis was attenuated from the early stage of treatment, and the effect was maintained for up to 52 weeks. In addition, the skin sclerosis in systemic sclerosis showed an improvement. Regarding the influence on type 1 diabetes, the required daily dose of insulin and hemoglobin A1c (HbA1c) levels decreased. To date, no studies have demonstrated the effectiveness of baricitinib on systemic sclerosis or type 1 diabetes. We report that baricitinib was effective for systemic sclerosis and type 1 diabetes, as well as for rheumatoid arthritis, for up to 52 weeks.

IgG4-related Pleuritis with Elevated Adenosine Deaminase in Pleural Effusion.

An 81-year-old man was admitted with bilateral pleural effusion. A clinical examination showed lymphocytic pleura effusion and elevated serum IgG4 levels, so that IgG4-related disease was suggested, whereas tuberculous pleurisy was suspected because of high adenosine deaminase (ADA) levels in the pleural effusion. A surgical pleural biopsy revealed that there were large numbers of IgG4-positive cells and IgG4/IgG positive cell ratio exceeded 40% in several sites. Accordingly, we diagnosed IgG4-related pleuritis and treated with the patient with glucocorticoid therapy. The ADA levels in pleural effusion can increase in IgG4-related pleuritis, and it is therefore important to perform a pleural biopsy.

Highly stabilized amorphous 3-bis(4-methoxyphenyl)methylene-2-indolinone (TAS-301) in melt-adsorbed products with silicate compounds.

3-Bis(4-Methoxyphenyl)methylene-2-indolinone (TAS-301) is a poorly water-soluble drug showing low oral bioavailability in rats and dogs. Previously, we reported that when a physical mixture of TAS-301 and a porous calcium silicate, Florite RE (FLR), was heated at high temperature (250 degrees C), the drug melted and was adsorbed by the FLR in an amorphous state, and that the preparation (melt-adsorbed product) showed a significantly increased solubility and dissolution rate, and a significantly enhanced oral bioavailability of the drug. The aim of the present study was to elucidate important factors for preparing a melt-adsorbed product showing greater stability of drug in an amorphous state. We examined the effects of the kind of adsorbent, drug/adsorbent ratio, heating conditions, and drug particle size on converting drug crystal into an amorphous state, the stability of amorphous state, and chemical stability of the drug in the melt-adsorbed products under a high temperature and high humidity condition (60 degrees C/80% RH, open). FLR, light anhydrous silicic acid and two types of hydrated silicon dioxides were tested as adsorbents. For the batch method, TAS-301 was converted into an amorphous state by heating TAS-301/adsorbents physical mixtures above the melting point of TAS-301 for more than 2 min. The amorphous state was most stabilized when FLR was used as an adsorbent and drug/FLR ratio was 1:0.5 and more. For the continuous method using the twin screw extruder that enables significantly larger scale manufacturing than batch method, TAS-301 melt-adsorbed products were able to produce when only FLR was used as adsorbent. The heating temperature was needed to be set above the melting point of TAS-301 to convert it into an amorphous state as well as batch method. The amorphous state was stabilized when drug/FLR ratio was 1:2 and more. The micronization of the drug decreased the stability of the amorphous state. These results indicate the importance of optimizing the above factors in the preparation of melt-adsorbed product.