Inhibition of the TIM-1 and -3 signaling pathway ameliorates disease in a murine model of rheumatoid arthritis.

Members of the T-cell immunoglobulin and mucin (TIM) family, which is crucial for T-cell function, are implicated in autoimmunity. TIM-1 and -3 play distinct roles in autoimmunity, with TIM-1 acting as a costimulatory molecule and TIM-3 regulating Th1 responses. We investigated the therapeutic potential of anti-TIM-1 (RMT1-10) and anti-TIM-3 (RMT3-23) antibodies in an autoimmune arthritis model. Zymosan A was used to induce arthritis in female SKG mice. The arthritis scores, histology, mRNA expression, cytokine levels, micro-computed tomography, and flow cytometry results were obtained. The application of RMT1-10 reduced the arthritis scores, histological damage, and CD4+ T-cell infiltrations, and it suppressed interleukin (IL)-6 and -17A and reduced TIM-3 mRNA expressions. RMT3-23 also lowered arthritis severity, improved histology, and reduced serum levels of tumor necrosis factor (TNF)-α and IL-17A. RMT3-23 inhibited intracellular TNF-α and IL-6 and early apoptosis. An amelioration of autoimmune arthritis was achieved by blocking the TIM-1 and -3 signaling pathways via RMT1-10 and RMT3-23 administration, leading to a widespread decrease in inflammatory cytokines. Both antibodies exhibited therapeutic effects, suggesting TIM-1 and -3 as potential targets for rheumatoid arthritis.

U-KIM-1 as a predictor of treatment response in lupus nephritis.

OBJECTIVE: Biomarkers of disease activity in lupus nephritis (LN) are in demand. This is because they may be useful in patients who are unable to undergo invasive kidney biopsy, as predictors of renal function, and for early detection of LN recurrence. The focus is on the measurement of urinary chemokines and cytokines, especially in urinary biomarkers, which are non-invasive and simple. In our previous report, we reported that kidney injury molecule-1 (KIM-1) is expressed in injured tubules and that the number of tubular-KIM-expressing positive cells correlates with renal pathology findings and also with urinary (u)-KIM-1 levels. However, there have been no reports examining the effect of u-KIM-1 levels on response to therapy, correlation with renal pathology, and usefulness as a predictor of renal function. METHODS: U-KIM-1 levels were measured by ELISA in 61 SLE patients. In 38 active LN who underwent renal biopsy, we also examined whether u-KIM-1 levels affected LN disease activity, renal histological findings, and predictors of renal function. RESULTS: In SLE patients, proteinuria and u-KIM-1 levels were elevated in active LN compared to inactive LN. U-KIM-1 and proteinuria decreased with intensified treatment. U-KIM-1 levels also correlated with the percentage of glomerular crescent formation in renal pathology. In addition, patients with higher baseline u-KIM-1 levels had significantly higher eGFR and lower LN disease activity at 12 months after treatment intensification. CONCLUSIONS: These data suggest that u-KIM-1 levels correlate with LN disease activity and renal histopathology findings and may be used as a predictor of treatment response.

Iguratimod versus salazosulfapyridine in rheumatoid arthritis patients with an inadequate response to methotrexate: Adjusted with propensity score matching.

OBJECTIVES: Methotrexate (MTX) is recommended as a first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD) for treating rheumatoid arthritis (RA). This retrospective study sought to identify an add-on csDMARD treatment strategy for RA patients with MTX-inadequate response (IR). METHODS: We collected the cases of RA patients treated with salazosulfapyridine (SASP) or iguratimod (IGU) as the additional csDMARD for MTX-IR during a 24-month follow-up. We performed propensity score matching to evaluate the retention rate, clinical efficacy, and safety profile (n = 54, each group). RESULTS: The retention rates at 24 months were 38.5% (MTX+SASP group) and 67.8% (MTX+IGU group). At 3 and 6 months, the MTX+IGU group's 28 joint-disease activity score (DAS28) was significantly decreased versus the MTX+SASP group, and at 3 months the MTX+IGU group's good-responder percentage (22.9%) was significantly higher versus the MTX+SASP group's good-responder percentage (10.7%). Conversely, compared to the MTX+SASP group, the MTX+IGU group showed a greater reduction in the estimated glomerular filtration rate from baseline during follow-up. CONCLUSIONS: IGU is a useful add-on csDMARD for RA patients with MTX-IR; its high retention rate and good clinical response make it a useful combination therapy for controlling RA disease activity. However, the renal function should be monitored during follow-up.

Deletion of Antigen-Presenting Cells in Lipopolysaccharide-Induced Acute Kidney Injury (AKI) Affects the Exacerbation and Repair in AKI.

The pathogenesis of acute kidney injury (AKI) is complex and involves various immune and inflammatory responses. Antigen-presenting cells such as macrophages and dendritic cells (DCs) were recently reported to have diverse functions in AKI depending on the pathogenesis and disease phase. Herein, we intraperitoneally administered liposomal clodronate (LC) to lipopoly-saccharide (LPS)-induced AKI model mice in order to deplete antigen-presenting cells (e.g., macrophages and DCs). After the LPS injection, the mice were divided into LC-treated (LPS + LC) and saline-treated groups (LPS), and the immune responses of macrophages and DCs in the acute and recovery phases were evaluated. The LPS + LC-treated group exhibited significantly suppressed renal macrophages and DC infiltration at 18 h and improved survival at 120 h after LPS injection. Via the depletion of macrophages and DC infiltrations, the serum and renal tissue inflammatory cytokines/chemokines were suppressed at 18 h and reversed at 120 h. Tubular kidney injury molecule-1 expression was decreased at 18 h and increased at 120 h. These findings indicate that LC administration suppressed tubular and interstitial injury in the acute phase of AKI and affected delayed tissue repair in the recovery phase. They are important for understanding innate and acquired immune responses in the therapeutic strategy for LPS-induced AKI.

Establishment of a patient-derived xenograft mouse model of pleomorphic leiomyosarcoma.

Soft tissue sarcomas are difficult to treat using chemotherapy owing to a current deficiency in candidate drugs for specific targets. Screening candidate compounds and analyzing therapeutic targets in sarcomas is insufficient, given the lack of an appropriate human sarcoma animal model to accurately evaluate their efficacy, as well as the lack of an adequate technical protocol for efficient transplantation and engraftment of sarcoma specimens in patient-derived xenograft (PDX) models. Accordingly, in this study, we sought to identify the optimal type of sarcoma and develop a protocol for generating a PDX model. We characterized a PDX mouse model using histopathological and immunohistochemical analyses to determine whether it would show pathological characteristics similar to those of human sarcomas. We achieved engraftment of one of the 10 transplanted sarcoma specimens, the xenografted tumor of which exhibited massive proliferation. Histologically, the engrafted sarcoma foci resembled a primary tumor of pleomorphic leiomyosarcoma and maintained their histological structure in all passages. Moreover, immunohistochemical analysis revealed the expression of specific markers of differentiation to smooth muscle, which is consistent with the features of leiomyosarcoma. We thus demonstrated that our pleomorphic leiomyosarcoma PDX mouse model mimics at least one aspect of human sarcomas, and we believe that this model will facilitate the development of novel therapies for sarcomas.

Fatal outcome in a patient under immunosuppressant therapy infected with human T-lymphotropic virus type 1 (HTLV-1), cytomegalovirus (CMV) and Strongyloides stercoralis: a case report.

BACKGROUND: Strongyloidiasis is a gastrointestinal parasitic infection caused by percutaneous infection with Strongyloides stercoralis. Digestive symptoms such as diarrhea and abdominal pain are the main manifestation, but serious infections such as septicemia, purulent meningitis, and bacterial pneumonia may occur in individuals harboring human T-lymphotropic virus type 1 (HTLV-1) or who are immunocompromised. Although coinfection with Strongyloides stercoralis and HTLV-1 can lead to chronic strongyloidiasis and a disseminated form of the disease, there is a high rate of response to the anthelmintic ivermectin. CASE PRESENTATION: We report a case of strongyloidiasis infection syndrome that was difficult to differentiate from immune reconstitution inflammatory syndrome (IRIS) for various reasons. The patient had been treated with the corticosteroids tacrolimus (Tac) and mycophenolate mofetil (MMF) for systemic lupus erythematosus (SLE) with lupus nephritis and pancytopenia. When the steroid was reduced, she developed cytomegalovirus (CMV) enteritis, and her respiratory status rapidly deteriorated immediately after the withdrawal of Tac and MMF. It was difficult to distinguish immune reconstitution inflammatory syndrome from strongyloidiasis infection syndrome because stool cultures were negative and eosinophils were not increased. Bronchoscopy revealed viable Strongyloides, leading to a diagnosis of strongyloidiasis infection syndrome, but the patient died despite treatment. CONCLUSIONS: Both corticosteroid therapy and HTLV-1 infection can be associated with a decrease of eosinophils, despite the presence of parasitic infection. In conclusion, even if multiple culture tests are negative, the risk of parasitic infection should be assessed in patients receiving immunosuppressants and steroids even in non-endemic areas.

Protective Effects of Recombinant Human Soluble Thrombomodulin on Lipopolysaccharide-Induced Acute Kidney Injury.

Thrombomodulin (TM) is a single transmembrane, multidomain glycoprotein receptor for thrombin, and is best known for its role as a cofactor in a clinically important natural anticoagulant pathway. In addition to its anticoagulant function, TM has well-defined anti-inflammatory properties. Soluble TM levels increase significantly in the plasma of septic patients; however, the possible involvement of recombinant human soluble TM (rTM) transduction in the pathogenesis of lipopolysaccharide (LPS)-induced nephrotoxicity, including acute kidney injury (AKI), has remained unclear. Mice were injected intraperitoneally with 15 mg/kg LPS. rTM (3 mg/kg) or saline was administered to the animals before the 3 and 24 h LPS-injection. At 24 and 48 h, blood urea nitrogen, the inflammatory cytokines in sera and kidney, and histological findings were assessed. Cell activation and apoptosis signal was assessed by Western blot analysis. In this study using a mouse model of LPS-induced AKI, we found that rTM attenuated renal damage by reducing both cytokine and cell activation and apoptosis signals with the accumulation of CD4+ T-cells, CD11c+ cells, and F4/80+ cells via phospho c-Jun activations and Bax expression. These findings suggest that the mechanism underlying these effects of TM may be mediated by a reduction in inflammatory cytokine production in response to LPS. These molecules might thereby provide a new therapeutic strategy in the context of AKI with sepsis.

Efficacy of iguratimod vs. salazosulfapyridine as the first-line csDMARD for rheumatoid arthritis.

Objectives: We retrospectively evaluated the retention rate and clinical responses following treatment for rheumatoid arthritis (RA) with iguratimod (IGU) vs. salazosulfapyridine (SASP) as the first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD).Methods: We analyzed 197 RA patients who were treated with IGU or SASP as the initial treatment in the 3-year study period. The retention rate, clinical response, the dosage and percent user of prednisolone (PSL), and safety profiles were evaluated.Results: At month 36, the retention rates of the IGU and SASP groups were 52.4 vs. 32.1%. The rate of responders (good or moderate response) at month 36 was 85.8 vs. 65.2% in the IGU and SASP groups, respectively. At month 36 for the IGU and SASP groups, the percentages of PSL users were 16.7 vs. 46.7%, and the PSL dosage was 0.3 mg/d vs. 2.0 mg/d, respectively. The cumulative rates of any adverse event (AE) at month 36 were 19.8 vs. 29.2% in the IGU and SASP groups, respectively.Conclusion: IGU is a useful first-line csDMARD treatment for RA patients, showing a high retention rate and good efficacy without an increased risk of serious AEs, including serious infections. Our findings also indicate a PSL dose-sparing effect of IGU treatment.

Protective effect and mechanism of IL-10 on renal ischemia-reperfusion injury.

Interleukin (IL)-10, a cytokine with anti-inflammatory effects, is produced by blood cells and cells of various organs. Ischemia-reperfusion injury (IRI) is a systemic inflammatory disease caused by a systemic circulation of pro-inflammatory cytokines and chemokines produced from blood cells or organs damaged by ischemia. Apoptosis, a key event after IRI, is correlated with the degree of injury. Here we investigated the effects and mechanism of IL-10 in renal IRI. Compared to wild-type (WT) mice with a renal IRI, IL-10 knockout (IL-10 KO) mice with IRI demonstrated decreased renal function as represented by blood urea nitrogen and serum creatinine, upregulated early acute kidney injury (AKI) biomarkers such as kidney injury molecule-1 (Kim-1), increased mRNA expression of the pro-inflammatory cytokines IL-1ß, IL-6, and IL-18 and a chemokine (regulated on activation, normal T cell expressed and secreted; RANTES), and increased expression of the pro-apoptosis factors Bax and cleaved caspase-3. When tubular epithelial cells (TECs) from IL-10 KO mice were put in a hypoxic state and added with recombinant IL-10, their expression of Bax decreased. Our findings demonstrated that IL-10 suppressed the production of pro-inflammatory cytokines, renal dysfunction, and the expression of pro-apoptosis factors after IRI.

Lipopolysaccharide-Induced Acute Kidney Injury Is Dependent on an IL-18 Receptor Signaling Pathway.

The proinflammatory cytokine interleukin (IL)-18 is an important mediator of the organ failure induced by endotoxemia. IL-18 (known as an interferon-gamma (IFN-γ) inducing factor), and other inflammatory cytokines have important roles in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). We investigated the effect of inflammatory cytokines and Toll-like receptor 4 (TLR4) expression, an event that is accompanied by an influx of monocytes, including CD4⁺ T cells and antigen-presenting cells (APCs) in IL-18Rα knockout (KO) mice and wild-type (WT) mice after LPS injection. In the acute advanced phase, the IL-18Rα KO mice showed a higher survival rate and a suppressed increase of blood urea nitrogen, increased levels of proinflammatory cytokines such as IFN-γ and IL-18, the infiltration of CD4⁺ T cells and the expression of kidney injury molecule-1 as an AKI marker. In that phase, the renal mRNA expression of the M1 macrophage phenotype and C-C chemokine receptor type 7 as the maturation marker of dendritic cells (DCs) was also significantly decreased in the IL-18Rα KO mice, although there were small numbers of F4/80⁺ cells and DCs in the kidney. Conversely, there were no significant differences in the expressions of mRNA and protein TLR4 after LPS injection between the WT and IL-18Rα KO groups. Our results demonstrated that the IL-18Rα-mediated signaling pathway plays critical roles in CD4⁺ T cells and APCs and responded more quickly to IFN-γ and IL-18 than TLR4 stimulation in the pathogenesis of LPS-induced AKI.

Estimation of the symptoms for GERD by GerdQ in the patients with rheumatic diseases.

OBJECTIVE: Gastroesophageal reflux disease (GERD) is one of the most common comorbidity in many diseases, but the frequency in rheumatic disease has not been well understood. METHODS: We investigated the prevalence of GERD by GerdQ in 530 rheumatic patients [systematic lupus erythematosus (SLE; n = 120), rheumatoid arthritis (RA; n = 117), polymyalgia rheumatica (PMR; n = 40), dermatomyositis and polymyositis (PM/DM; n = 38), systemic scleroderma (SSc; n = 37), mixed connective tissue disease (MCTD; n = 18), Behçet disease (BD; n = 17), adult onset still disease (AOSD; n = 14), and other rheumatic diseases (n = 129)]. RESULTS: The mean GerdQ scores of patients was 6.2 ± 1.8, respectively, and no significant differences were observed between all patients. However, the GERD prevalence in SSc and BD was increased compared to that in SLE, RA, PMR, PM/DM, MCTD, and AOSD. In no medication of proton pump inhibitors (PPIs), a significant increase in the risk of GERD symptoms was 2.5 times compared with that in the medication of PPIs in all patients by multivariable regression analysis. On the other hand, there were no increased risks of GERD symptoms with corticosteroids. CONCLUSION: In rheumatic diseases, GerdQ would be the useful tool of diagnosis GERD, regardless whether the patients complain or not about gastrointestinal (GI) symptoms.

Signaling Rho-kinase mediates inflammation and apoptosis in T cells and renal tubules in cisplatin nephrotoxicity.

Nephrotoxicity is a frequent complication of cisplatin-induced chemotherapy, in which T cells are known to promote acute kidney injury (AKI). Apoptosis and necrosis of tubules and inflammatory events also contribute to the nephrotoxicity. A delineation of the mechanisms that underlie the inappropriate renal and tubular inflammation can thus provide important insights into potential therapies for cisplatin-induced AKI. Rho-kinases are known to act as molecular switches controlling several critical cellular functions, including cell migration, cytokine production, and apoptosis. Here, we show that the Rho-kinase inhibitor fasudil attenuated cisplatin nephrotoxicity, resulting in less histological damage, improved renal function, and the infiltration of fewer leukocytes into the kidney. Renal nuclear factor-κB activation and apoptosis were reduced, and the expressions of proinflammatory renal cytokine and chemokine mRNA were decreased. Urinary and renal kidney injury molecule-1 (Kim-1) expression was also reduced, a finding that is consistent with diminished kidney injury. In the current study, we also showed that fasudil could be protective of the impaired tubules. In vitro, fasudil reduced the apoptosis (annexin-V+PI cells) and cytokine production (tumor necrosis factor+ cells) in T cells and the apoptosis (annexin-V+PI cells) and tubular damage (Kim-1+ cells) in proximal tubular cells by flow cytometric analysis. As Rho-kinase plays an important role in promoting cisplatin nephrotoxicity, inhibiting Rho-kinase may be a therapeutic strategy for preventing cisplatin-induced AKI.

The pathological role of IL-18Rα in renal ischemia/reperfusion injury.

Interleukin (IL)-18 is a proinflammatory cytokine produced by leukocytes and parenchymal cells (eg, tubular epithelial cells (TECs), mesangial cells, and podocytes). IL-18 receptor (IL-18R) is expressed on these cells in the kidney during ischemia/reperfusion injury (IRI), but its role in this injury is unknown. Fas/Fas ligand (FasL) is also involved in the pathogenesis of renal IRI via tubular apoptosis. In addition, IL-18 enhances the expression of FasL on TECs, but the mechanism underlying this enhancement is not known. Here we used IL-18Rα-deficient mice to explore the pathological role of IL-18Rα in renal IRI. We found that compared to wild-type (WT) mice with renal IRI as an acute kidney injury (AKI), the IL-18Rα-deficient mice demonstrated decreased renal function (as represented by blood urea nitrogen), tubular damage, an increased accumulation of leukocytes (CD4+ T cells, neutrophils, and macrophages), upregulated early AKI biomarkers (ie, urinary kidney injury molecule-1 levels), and increased mRNA expressions of proinflammatory cytokines (IL-1ß, IL-12p40, and IL-18) and chemokines (intercellular adhesion molecule-1 and CCL2/monocyte chemoattractant protein-1). The mRNA expression of FasL in the kidney was increased in the IL-18Rα-deficient mice compared to the WT mice. The adoptive transfer of splenocytes by WT mice led to decreased renal IRI compared to the IL-18Rα-deficient mice. In vitro, the mRNA expression of FasL on TECs was promoted in the presence of recombinant IL-18. These data reveal that IL-18Rα has an anti-inflammatory effect in IRI-induced AKI. Above all, IL-18 enhanced the inflammatory mechanisms and the apoptosis of TECs through the Fas/FasL pathway by blocking IL-18Rα.

Endogenous Tim-1 promotes severe systemic autoimmunity and renal disease MRL-Fas(lpr) mice.

The T-cell immunoglobulin mucin 1, also known as kidney injury molecule-1, modulates CD4+ T-cell responses and is also expressed by damaged proximal tubules within the kidney. Both Th subset imbalance (Th1/Th2/Th17) and regulatory T-cell and B-cell alterations contribute to the pathogenesis of autoimmune disease. This study investigated the effects of an inhibitory anti-T-cell immunoglobulin mucin 1 antibody (RMT1-10) in lupus-prone MRL-Fas(lpr) mice. MRL-Fas(lpr) mice were treated with RMT1-10 or a control antibody intraperitoneally twice weekly from 3 mo of age for 16 wk. RMT1-10 treatment significantly improved survival, limited the development of lymphadenopathy and skin lesions, preserved renal function and decreased proteinuria, reduced serum anti-DNA antibody levels, and attenuated renal leukocyte accumulation. Th1 and Th17 cellular responses systemically and intrarenally were reduced, but regulatory T and B cells were increased. RMT1-10 treatment also reduced glomerular immunoglobulin and C3 deposition and suppressed cellular proliferation and apoptosis. Urinary excretion and renal expression of kidney injury molecule-1 was reduced, reflecting diminished interstitial injury. As RMT1-10 attenuated established lupus nephritis, manipulating immune system T-cell immunoglobulin mucin 1 may represent a therapeutic strategy in autoimmune diseases affecting the kidney.

Geriatric Nutritional Risk Index predicts bleeding event in patients with heart failure.

AIMS: We aimed to elucidate the association between malnutrition and the occurrence of bleeding events in patients with heart failure. METHODS AND RESULTS: We evaluated the nutritional status of patients with heart failure [n = 2044, median (inter-quartile range) age 69.0 (59.0-78.0) years, 1209 (59.1%) males] using the Geriatric Nutritional Risk Index (GNRI). The primary endpoint was a composite of bleeding events such as haemorrhagic stroke or gastrointestinal bleeding. According to the survival classification and regression tree analysis, the accurate cut-off point of GNRI for predicting the primary endpoint was 106.2. We divided the patients into two groups based on GNRI levels: high GNRI group (GNRI ≥ 106.2, n = 606, 29.6%) and low GNRI group (GNRI < 106.2, n = 1438, 70.4%). We compared the patients' characteristics and prognosis between the two groups. The low GNRI group was older [72.0 (63.0-79.0) vs. 63.0 (53.0-73.0) years, P < 0.001] and had a lower prevalence of male sex (56.9% vs. 64.5%, P = 0.001). There were no differences in the use of antiplatelet agents and anticoagulants between the two groups. Levels of B-type natriuretic peptide were higher [321.1 (123.3-667.4) vs. 111.6 (42.6-235.4) pg/mL, P < 0.001] and levels of haemoglobin were lower [12.4 (10.8-13.7) vs. 14.2 (12.9-15.4) g/dL, P < 0.001] in the low GNRI group. The Kaplan-Meier analysis demonstrated that bleeding event rates were higher in the low GNRI group (log-rank P < 0.001). The multivariable Cox proportional hazard analysis revealed that low GNRI (hazard ratio 1.952, 95% confidence interval 1.002-3.805, P = 0.049) was associated with bleeding events. CONCLUSIONS: Heart failure patients with poor nutritional status, determined by GNRI under 106.2, experienced high bleeding event rates. Comprehensive management is required to avoid bleeding event in those populations.

A new test for evaluation of marginal cognitive function deficits in idiopathic normal pressure hydrocephalus through expressing texture recognition by sound symbolic words.

Introduction: The number of dementia patients is increasing with population aging. Preclinical detection of dementia in patients is essential for access to adequate treatment. In previous studies, dementia patients showed texture recognition difficulties. Onomatopoeia or sound symbolic words (SSW) are intuitively associated with texture impressions and are less likely to be affected by aphasia and description of material perception can be easily obtained. In this study, we aimed to create a test of texture recognition ability expressed by SSW to detect the presence of mild cognitive disorders. Methods: The sound symbolic words texture recognition test (SSWTRT) is constructed from 12 close-up photos of various materials and participants were to choose the best SSW out of 8 choices to describe surface texture in the images in Japanese. All 102 participants seen in Juntendo University Hospital from January to August 2023 had a diagnosis of possible iNPH (age mean 77.9, SD 6.7). The answers were scored on a comprehensive scale of 0 to 1. Neuropsychological assessments included MMSE, FAB, and the Rey Auditory Verbal Learning Test (RAVLT), Pegboard Test, and Stroop Test from the EU-iNPH Grading Scale (GS). In study 1 the correlation between SSWTRT and the neuropsychological tests were analyzed. In study 2, participants were divided into two groups: the Normal Cognition group (Group A, n = 37) with MMSE scores of 28 points or above, and the Mild Cognitive Impairment group (Group B, n = 50) with scores ranging from 22 to 27 points, and its predictability were analyzed. Results: In study 1, the total SSWTRT score had a moderate correlation with the neuropsychological test results. In study 2, there were significant differences in the SSWTRT scores between groups A and B. ROC analysis results showed that the SSWTR test was able to predict the difference between the normal and mildly impaired cognition groups. Conclusion: The developed SSWTRT reflects the assessment results of neuropsychological tests in cognitive deterioration and was able to detect early cognitive deficits. This test not only relates to visual perception but is likely to have an association with verbal fluency and memory ability, which are frontal lobe functions.

Safety of Janus kinase inhibitors compared to biological DMARDs in patients with rheumatoid arthritis and renal impairment: the ANSWER cohort study.

Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m2): 2893 patients; CKDa group (eGFR 45-60 mL/min/1.73 m2): 551; and CKDb group (eGFR < 45 mL/min/1.73 m2): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09-0.61), IL-6Ri: 0.34 (0.14-0.81), CTLA-4-Ig: 0.36 (0.15-0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m2). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs.

Blockade of IL-18Rα-mediated signaling pathway exacerbates neutrophil infiltration in imiquimod-induced psoriasis murine model.

Psoriasis is an immune-mediated inflammatory disease of the skin, which is characterized by epidermal hyperkeratosis and neutrophil infiltration. The interleukin (IL)-17/IL-23 pathway and associated cytokines play major roles in the pathogenesis and exacerbation of psoriasis. The IL-18/IL-18 receptor (R) α signaling pathway is important for Th1 cytokine production and differentiation of Th1 cells; however, its role in the pathogenesis of psoriasis remains unknown. In this study, we investigated the effect of the IL-18Rα-mediated signaling pathway in the pathogenesis of psoriasis in Il18ra-deficient mice (Il18ra-/-) and wild-type imiquimod (IMQ)-induced psoriatic dermatitis model mice. Blocking this pathway exacerbated IMQ-induced psoriatic skin inflammation. Il18ra deficiency led to significant increases in the levels of IL-1ß, IL-6, IL-8, IL-17A, IL-23, and chemokine (C-X-C motif) ligand 2 in skin lesions. Gr1-positive cells highly infiltrated psoriatic skin lesions in Il18ra-/- mice compared to those in wild-type mice. Citrullinated histone H3-positive area was relatively broad in Il18ra-/- mice. These results suggest that IL-18Rα-mediated signaling pathways may inhibit psoriatic skin inflammation by regulating infiltration and activation of neutrophil and other innate immune cells.

The Impact of Early Optimization of Infliximab Blood Concentrations >1 µg/mL on Therapeutic Effectiveness in Rheumatoid Arthritis.

BACKGROUND: Infliximab is a human-murine chimeric monoclonal IgG antibody against tumor necrosis factor that is used in combination with methotrexate for the treatment of moderate to severe rheumatoid arthritis (RA). The trough concentration of serum infliximab required to control disease activity in RA is ≥1 µg/mL, and we investigated whether this trough concentration can predict the effectiveness of RA treatment. METHODS: We retrospectively analyzed the cases of 76 patients with RA. The REMICHECK Q® (REMIQ) is a kit that can check for serum infliximab concentrations. Infliximab concentrations >1 µg/mL at 14 weeks after an initial infliximab induction is considered REMIQ-positive, otherwise considered REMIQ-negative. Here, we determined the retention rates and investigated the clinical and serologic features of REMIQ-positive and REMIQ-negative patients. RESULTS: At 14 weeks, significantly more of the REMIQ-positive patients (n = 46) were responders compared to the non-responders (n = 30). The retention rate at 54 weeks was also significantly higher in the REMIQ-positive group versus the negative group. After 14 weeks, more patients in the REMIQ-negative group were considered inadequate responders, and their infliximab doses were escalated. At baseline, the REMIQ-positive group had significantly lower C-reactive protein (CRP) levels compared to the negative group. Cox regression analysis with multiple variables showed that the positivity of REMIQ (hazard ratio [HR] 2.10 and 95% confidence interval [CI]: 1.55-5.71) at baseline was associated with the achievement of low disease activity. The positivities of rheumatoid factor and anti-CCP antibody at baseline were associated with the achievement of remission with infliximab treatment (HR 0.44, 95% CI: 0.09-0.82 and HR 0.35, 95% CI: 0.04-0.48, respectively). CONCLUSIONS: The results of this study suggest that the control of RA disease activity may be facilitated by using the REMIQ kit at 14 weeks to check whether it is necessary to increase a patient's infliximab dose to ensure a therapeutic blood concentration that will help the patient achieve low disease activity.

Persistent Hypochloremia Is Associated with Adverse Prognosis in Patients Repeatedly Hospitalized for Heart Failure.

BACKGROUND: Hypochloremia reflects neuro-hormonal activation in patients with heart failure (HF). However, the prognostic impact of persistent hypochloremia in those patients remains unclear. METHODS: We collected the data of patients who were hospitalized for HF at least twice between 2010 and 2021 (n = 348). Dialysis patients (n = 26) were excluded. The patients were divided into four groups based on the absence/presence of hypochloremia (<98 mmol/L) at discharge from their first and second hospitalizations: Group A (patients without hypochloremia at their first and second hospitalizations, n = 243); Group B (those with hypochloremia at their first hospitalization and without hypochloremia at their second hospitalization, n = 29); Group C (those without hypochloremia at their first hospitalization and with hypochloremia at their second hospitalization, n = 34); and Group D (those with hypochloremia at their first and second hospitalizations, n = 16). RESULTS: a Kaplan-Meier analysis revealed that all-cause mortality and cardiac mortality were the highest in Group D compared to the other groups. A multivariable Cox proportional hazard analysis revealed that persistent hypochloremia was independently associated with both all-cause death (hazard ratio 3.490, p < 0.001) and cardiac death (hazard ratio 3.919, p < 0.001). CONCLUSIONS: In patients with HF, prolonged hypochloremia over two hospitalizations is associated with an adverse prognosis.