Real-world comparative study of drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis.

BACKGROUND: Janus kinase (JAK) inhibitors (JAKis) are effective therapeutic agents against rheumatoid arthritis (RA). However, patients having RA with particular risk factors may have a higher incidence of adverse effects (AEs), including major cardiovascular events (MACE) and infections. In this multicenter cohort study, we aimed to clarify the risk factors affecting the drug retention of JAKis in patients with RA. METHODS: We retrospectively evaluated patients with RA who received their first JAKi (tofacitinib, baricitinib, upadacitinib, or filgotinib) at our institute. The clinical outcomes, including AEs, were recorded, particularly MACE and serious infections. The drug retention rates were analyzed using the Kaplan-Meier method, and risk factors affecting drug retention rates were determined using a multivariable Cox regression hazards model. RESULTS: Overall 184 patients with RA receiving their first use of baricitinib (57.6%), tofacitinib (23.9%), upadacitinib (12.0%), or filgotinib (6.5%) were included in this study. Fifty-six (30.4%) patients discontinued JAKi treatment owing to ineffectiveness (9.2%) or AEs, including infections (21.2%). The overall drug retention rates were significantly lower in patients treated with pan-JAKi than in those treated with JAK1 inhibitors (p = 0.03). In the Cox regression model, the presence of baseline high RA disease activity, use of glucocorticoid and treatments with pan-JAKis were associated with reduced drug retention rates of JAKis (p < 0.001, p = 0.01 and 0.04, respectively). Pan-JAKi treated patients with high disease activity had significantly lower drug retention rates (p < 0.001). CONCLUSIONS: In a real-world setting, the drug retention rates of JAKis were reduced mainly by treatment discontinuation owing to AEs. Treatment with pan-JAKis and high baseline RA disease activity were identified as predictive factors for the discontinuation of JAKis. Lower drug retention rates were found in patients receiving pan-JAKis with high disease activity than in those without high disease activity.

A case of reinitiation of modified electroconvulsive therapy 2 weeks after modified electroconvulsive therapy-induced Takotsubo cardiomyopathy in a male patient with major depressive disorder.

Background: Takotsubo cardiomyopathy (TCM) is a left ventricular dysfunction resembling acute coronary syndrome. Its prognosis is generally favorable; however, a subset of patients may present with severe complications. TCM is a rare side-effect of modified electroconvulsive therapy (ECT); it has been reported in 22 female and two male patients. Eight cases of ECT reinitiation after TCM have been reported (all females), with the shortest duration being 3 weeks. Case Presentation: We report the case of a 61-year-old man with a history of major depressive disorder and no history of heart disease or previous ECT treatment. Antidepressants had been ineffective, and ECT was indicated. After the third ECT session, the patient complained of chest pain and shortness of breath. Electrocardiography revealed ST elevation, and catheter angiography was used to diagnose TCM. The patient had mild heart failure but remained stable. Recognizing that ECT was effective, the patient asked for it to be reinitiated. We confirmed that the cardiac function had been normalized, applied a bisoprolol fumarate patch as a preventive measure, and reinitiated ECT 14 days after the onset of TCM. ECT was performed five times, with no recurrence of TCM and a marked improvement in depression. Conclusion: We describe a male patient with major depressive disorder who underwent reinitiation of ECT 2 weeks after ECT-induced TCM. Therefore, TCM should be recognized as a side-effect of ECT, even in men. Moreover, depending on whether the patient's condition is stable, ECT can be successfully performed in patients with TCM.

Highly-integrable analogue reservoir circuits based on a simple cycle architecture.

Physical reservoir computing is a promising solution for accelerating artificial intelligence (AI) computations. Various physical systems that exhibit nonlinear and fading-memory properties have been proposed as physical reservoirs. Highly-integrable physical reservoirs, particularly for edge AI computing, has a strong demand. However, realizing a practical physical reservoir with high performance and integrability remains challenging. Herein, we present an analogue circuit reservoir with a simple cycle architecture suitable for complementary metal-oxide-semiconductor (CMOS) chip integration. In several benchmarks and demonstrations using synthetic and real-world data, our developed hardware prototype and its simulator exhibit a high prediction performance and sufficient memory capacity for practical applications, showing promise for future applications in highly integrated AI accelerators.

Incidence Rates of Infections in Rheumatoid Arthritis Patients Treated with Janus Kinase or Interleukin-6 Inhibitors: Results of a Retrospective, Multicenter Cohort Study.

Objective: This study aimed to compare the incidence rates (IRs) of infections, including herpes zoster (HZ), in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis) or interleukin-6 inhibitors (IL-6is). Methods: We retrospectively analyzed 444 RA patients treated using IL-6is (n = 283) or JAKis (n = 161). After adjusting for clinical characteristic imbalances by propensity score matching (PSM), we compared the IRs of infections including HZ between the JAKi and IL-6i groups. Results: Observational period: 1423.93 patient years (PY); median observational period: 2.51 years. After PSM, incidence rate ratios comparing JAKi with IL-6i were 3.45 (95% confidence interval [CI]: 1.48-9.04) for serious infections other than HZ indicating that the JAKi-treated group was more likely to develop serious infection than the IL-6i-treated group. Multivariate Cox regression analyses revealed that the use of prednisolone > 5.0 mg/day, coexisting interstitial lung disease (ILD), and diabetes mellitus (DM) were independent risk factors for serious infections. The crude IR for HZ was significantly higher in the JAKi group, but the difference between groups was not significant (IRR: 2.83, 95% CI: 0.87-10.96) in PSM analysis. Unadjusted and PSM analyses performed in our study showed increased IRs of serious infections in patients with RA treated with JAKis compared with those treated with IL-6is. Conclusions: The presence of ILD or DM and the use of prednisolone were found to be independent risk factors for serious infection in RA patients treated using JAKis. Whereas the IRs for HZ after PSM were not significantly different between the JAKi and IL-6i groups.

Acute adverse events of ultra-hypofractionated whole-breast irradiation after breast-conserving surgery for early breast cancer in Japan: an interim analysis of the multi-institutional phase II UPBEAT study.

BACKGROUND: The applicability of ultra-hypofractionated (ultra-HF) whole-breast irradiation (WBI) remains unknown in Japanese women. This study aimed to evaluate the safety and efficacy of this approach among Japanese women and report the results of an interim analysis performed to assess acute adverse events (AEs) and determine whether it was safe to continue this study. METHODS: We enrolled Japanese women with invasive breast cancer or ductal carcinoma in situ who had undergone breast-conserving surgery, were aged ≥ 40 years, had pathological stages of Tis-T3 N0-N1, and had negative surgical margins. Ultra-HF-WBI was delivered at 26 Gy in five fractions over one week. When the number of enrolled patients reached 28, patient registration was paused for three months. The endpoint of the interim analysis was the proportion of acute AEs of grade ≥ 2 (Common Terminology Criteria for Adverse Events v5.0) within three months. RESULTS: Of the 28 patients enrolled from seven institutes, 26 received ultra-HF-WBI, and 2 were excluded due to postoperative infections. No AEs of grade ≥ 3 occurred. One patient (4%) experienced grade 2 radiation dermatitis, and 18 (69%) had grade 1 radiation dermatitis. The other acute grade 1 AEs experienced were skin hyperpigmentation (n = 10, 38%); breast pain (n = 4, 15%); superficial soft tissue fibrosis (n = 3, 12%); and fatigue (n = 1, 4%). No other acute AEs of grade ≥ 2 were detected. CONCLUSIONS: Acute AEs following ultra-HF-WBI were within acceptable limits among Japanese women, indicating that the continuation of the study was appropriate.

Time-series blood cytokine profiles correlate with treatment responses in triple-negative breast cancer patients.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype. Partly due to its heterogeneity, it is currently challenging to stratify TNBC patients and predict treatment outcomes. METHODS: In this study, we examined blood cytokine profiles of TNBC patients throughout treatments (pre-treatment, during chemotherapy, pre-surgery, and 1 year after the surgery in a total of 294 samples). We analyzed the obtained cytokine datasets using weighted correlation network analyses, protein-protein interaction analyses, and logistic regression analyses. RESULTS: We identified five cytokines that correlate with good clinical outcomes: interleukin (IL)-1α, TNF-related apoptosis-inducing ligand (TRAIL), Stem Cell Factor (SCF), Chemokine ligand 5 (CCL5 also known as RANTES), and IL-16. The expression of these cytokines was decreased during chemotherapy and then restored after the treatment. Importantly, patients with good clinical outcomes had constitutively high expression of these cytokines during treatments. Protein-protein interaction analyses implicated that these five cytokines promote an immune response. Logistic regression analyses revealed that IL-1α and TRAIL expression levels at pre-treatment could predict treatment outcomes in our cohort. CONCLUSION: We concluded that time-series cytokine profiles in breast cancer patients may be useful for understanding immune cell activity during treatment and for predicting treatment outcomes, supporting precision medicine. TRIAL REGISTRATION: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with the unique trial number UMIN000023162. The association Japan Breast Cancer Research Group trial number is JBCRG-22. The clinical outcome of the JBCRG-22 study was published in Breast Cancer Research and Treatment on 25 March 2021. https://doi.org/10.1007/s10549-021-06184-w .

Reducing the use of psychotropics in a convalescent rehabilitation ward.

AIMS: Many patients who are transferred to the convalescent rehabilitation ward of Kawasaki Kokoro Hospital (hereinafter, our hospital) are on psychotropics prescribed for delirium by their physicians at acute care hospitals. In this study, psychiatrists and pharmacists collaborated with rehabilitation physicians to reduce the use of psychotropics. METHODS: The basic information and psychotropics prescription statuses of 88 patients discharged from the convalescent rehabilitation ward of our hospital between April 1, 2021 and March 31, 2022 were derived from their medical records. RESULTS: At admission, psychotropics were prescribed to 55 patients and the number of prescribed drugs was 2 (median). At discharge, psychotropics were prescribed to 41 patients and the number of prescribed drugs was 1 (median), showing a significant decrease (p < 0.05). Compared with those at admission, prescribed psychotropic doses at discharge were significantly higher for lemborexant but significantly lower for antipsychotics, benzodiazepine/nonbenzodiazepine hypnotics, antidepressants, suvorexant, ramelteon, and sodium valproate (p < 0.05). CONCLUSIONS: These results suggest that it may be possible to reduce the types and doses of psychotropics prescribed at acute care hospitals in convalescent rehabilitation wards. However, further investigation is needed because the number of patients in this study was limited, and selection bias due to different patient characteristics cannot be ruled out.

Comparison of cisplatin-based versus standard preoperative chemotherapy in patients with operable triple-negative breast cancer: propensity score matching and inverse probability of treatment weighting analysis.

PURPOSE: The efficacy of carboplatin is non-equivalent to that of cisplatin (CDDP) for various tumor types in curative settings. However, the role of CDDP in operable triple-negative breast cancer (TNBC) patients remains unknown. We conducted a multicenter observational study to examine the effects of CDDP added to preoperative chemotherapy in patients with TNBC. METHODS: This retrospective study consecutively included previously untreated patients with stage I-III TNBC treated with preoperative chemotherapy with or without CDDP. The primary endpoint was distant disease-free survival (DDFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to minimize confounding biases in comparisons between the two groups. RESULTS: A total of 138 patients were enrolled in the study. Of these, 52 were in the CDDP group and 86 in the non-CDDP group. DDFS was significantly better in the CDDP group than in the non-CDDP group (unadjusted hazard ratio (HR) 0.127 and p < 0.001, PSM HR 0.141 and p < 0.003, IPTW HR 0.123 and p = < 0.001). Furthermore, among the patients with residual cancer burden (RCB) class II/III, DDFS was better in the CDDP group than in the non-CDDP group (unadjusted HR 0.192 and p = 0.013, PSM HR 0.237 and p = 0.051, IPTW HR 0.124 and p = 0.059). CONCLUSION: Our study showed that CDDP-containing regimens achieved favorable prognoses in patients with operable TNBC, especially for the RCB class II/III population. Confirmative studies are warranted to elucidate the role of CDDP in TNBC treatment.

Behavioral stress and antidepressant treatments altered hippocampal expression of Nogo signal-related proteins in rats.

Some immune molecules including neurite outgrowth inhibitor (Nogo) ligands and their receptor（Nogo receptor-1: NgR1）are expressed at the neuronal synaptic sites. Paired immunoglobulin-like receptor B (PirB) is another Nogo receptor that also binds to major histocompatibility complex I and ß-amyloid and suppresses dendritic immune cell functions and neuronal plasticity in the central nervous system. Augmenting structural and functional neural plasticity by manipulating the Nogo signaling pathway is a novel promising strategy for treating brain ischemia and degenerative processes such as Alzheimer's disease. In recent decades psychiatric research using experimental animals has focused on the attenuation of neural plasticity by stress loadings and on the enhanced resilience by psychopharmacological treatments. In the present study, we examined possible expressional alterations in Nogo signal-related proteins in the rat hippocampus after behavioral stress loadings and antidepressant treatments. To validate the effectiveness of the procedures, previously reported increase in brain-derived neurotrophic factor (BDNF) by ECS or ketamine administration and decrease of BDNF by stress loadings are also shown in the present study. Significant increases in hippocampal NgR1 and PirB expression were observed following chronic variable stress, and a significant increase in NgR1 expression was observed under a single prolonged stress paradigm. These results indicate a possible contribution of enhanced Nogo signaling to the attenuation of neural plasticity in response to stressful experiences. Additionally, the suppression of hippocampal NgR1 expression using electroconvulsive seizure treatment and administration of subanesthetic dose of ketamine supported the increased neural plasticity induced by the antidepressant treatments.

Real-World Effectiveness of Belimumab in Patients with Active Lupus.

This study evaluated the real-world effectiveness of belimumab (BLM) in the treatment of systemic lupus erythematosus (SLE) patients with moderate to high disease activity. This retrospective cohort study enrolled 129 Japanese patients with moderate to high SLE disease activity who received BLM between January 2013 and March 2023. The clinical outcomes, including the flare-free survival, SLE Disease Activity Index 2000 (SLEDAI-2K) score, and prednisone-equivalent dose, in the BLM and mycophenolate mofetil (MMF) treatment groups were compared before and after treatment. Safety data for BLM were collected. Additionally, we compared the effectiveness of BLM and intravenous cyclophosphamide (IV-CY) treatment using the stabilized inverse probability of treatment weighting (IPTW) method based on the propensity scores. This observational study enrolled 129 patients with moderate/severe SLE: 48 patients received belimumab, 45 received IV-CY, and 36 received MMF and prednisolone for remission induction therapy. The median follow-up for the BLM group was 17.0 months. Among them, 19 received BLM plus MMF. BLM significantly reduced the mean SLEDAI-2K (from mean baseline to 52 weeks: 49.2% reduction from 12.8 to 6.5) and prednisone daily dose (from mean baseline to 52 weeks: 21.9% reduction from 12.8 to 10.0 mg/day). The flare-free survival at 52 weeks was not significantly different between the BLM and MMF groups. There was no significant difference in the flare-free survival rates or reduction rates of the SLEDAI-2K between the patients treated with BLM and those treated with BLM plus MMF. In the propensity score-matched comparative analyses, there was no significant difference in the flare-free survival rates or an estimated decline in the SLEDAI-2K scores between the patients with lupus treated with BLM and IV-CY. BLM may be a promising alternative treatment option for lupus patients with moderate or high disease activity who do not respond to conventional treatments.

Cellular senescence triggers intracellular acidification and lysosomal pH alkalinized via ATP6AP2 attenuation in breast cancer cells.

Several chemotherapeutic drugs induce senescence in cancer cells; however, the mechanisms underlying intracellular pH dysregulation in senescent cells remain unclear. Adenosine triphosphatase H+ transporting accessory protein 2 (ATP6AP2) plays a critical role in maintaining pH homeostasis in cellular compartments. Herein, we report the regulatory role of ATP6AP2 in senescent breast cancer cells treated with doxorubicin (Doxo) and abemaciclib (Abe). A decline in ATP6AP2 triggers aberrant pH levels that impair lysosomal function and cause immune profile changes in senescent breast cancer cells. Doxo and Abe elicited a stable senescent phenotype and altered the expression of senescence-related genes. Additionally, senescent cells show altered inflammatory and immune transcriptional profiles due to reprogramming of the senescence-associated secretory phenotype. These findings elucidate ATP6AP2-mediated cellular pH regulation and suggest a potential link in immune profile alteration during therapy-induced senescence in breast cancer cells, providing insights into the mechanisms involved in the senescence response to anticancer therapy.

Safety of JAK and IL-6 inhibitors in patients with rheumatoid arthritis: a multicenter cohort study.

Background: The ORAL Surveillance trial showed a potentially higher incidence of malignancy and major adverse cardiovascular events (MACEs) associated with tofacitinib than those associated with tumor necrosis factor (TNF) inhibitors (TNFis). However, few studies have compared the safety of non-TNFis or other Janus kinase (JAK) inhibitors (JAKis). This study was aimed at comparing the incidence rates (IRs) of malignancies and MACEs in patients with rheumatoid arthritis (RA) treated using interleukin-6 (IL-6) inhibitors (IL-6is) or JAKis. Methods: We retrospectively analyzed 427 patients with RA who were treated using an IL-6i (n = 273) or a JAKi (n = 154). We determined the IRs of malignancy and MACEs, and the standardized incidence ratio (SIR) of malignancies and investigated factors related to malignancy and MACEs. After adjusting the clinical characteristic imbalance by propensity score matching (PSM), we compared the IRs of adverse events between the JAKi and IL-6i groups. Results: After PSM, the observational period was determined to be 605.27 patient-years (PY), and the median observational period was determined to be 2.28 years. We identified seven cases of malignancy (IR: 2.94 per 100 PY) in the JAKi-treated group and five cases (IR: 1.36 per 100 PY) in the IL-6i-treated group after PSM. The IR of MACEs was 2.56 and 0.83 (per 100 PY) in the JAKi- and IL-6i-treated groups. The IRRs of JAKi-treated patients versus IL-6i-treated patients were 2.13 (95% confidence interval (CI): 0.67-7.42) for malignancy and 3.03 (95% CI: 0.77-15.21) for MACE. There were no significant differences in IRR for malignancy and MACE between both groups after PSM. Univariate and multivariable Cox regression analyses revealed that older age and JAKi use were independent risk factors for malignancy, while older age, hypertension, and JAKi use were independent risk factors for MACEs. The overall malignancy SIR was significantly higher in the JAKi-treated group compared to the general population (2.10/100 PY, 95% CI: 1.23-2.97). Conclusion: The IRs of malignancy and MACE in patients with RA after PSM were comparable between IL-6i-treated and JAKi-treated patients. However, the SIR of malignancy in JAKi treatment was significantly higher than in the general population; therefore, further safety studies comparing JAKi to non-TNFi biologic disease-modifying antirheumatic drugs (bDMARDs) are needed.

Systemic Lupus Erythematosus and Antiphospholipid Syndrome Accompanied by Mixed-Type Autoimmune Hemolytic Anemia.

Systemic lupus erythematosus (SLE) is an autoimmune disease that leads to a wide spectrum of clinical and immunological abnormalities. Hematologic abnormalities are an important manifestation of SLE. The incidence of autoimmune hemolytic anemia (AIHA) has been reported in approximately 10% of patients with SLE. Among them, mixed-type AIHA, which is caused by warm autoantibodies and cold hemagglutinin, is relatively rarely reported. We report the case of a 72-year-old woman, who was admitted to our hospital due to shortness of breath, jaundice, and severe anemia, with SLE and antiphospholipid syndrome (APS) complicated by mixed-type AIHA. Laboratory data revealed severe hemolytic anemia (low hemoglobin, high indirect bilirubin, and high lactate dehydrogenase levels), low complement levels, and the presence of antinuclear antibodies and lupus anticoagulant. Imaging results revealed pleural effusion and pulmonary embolisms, and echocardiogram revealed high estimated right ventricular pressure. She was diagnosed with SLE and APS complicated by mixed-type AIHA based on positive direct antiglobulin and cold agglutinin tests (thermal amplitude ≥30°C). As mixed-type AIHA is a severe and chronic condition, she was administered potent treatments with immunosuppressants. However, because she was a carrier of human T-cell leukemia virus type-1, only a moderate amount of prednisolone was administered. She refused to take warfarin. Fortunately, her symptoms and laboratory abnormalities improved after prednisolone administration, and no relapse occurred after tapering the prednisolone dose. Although mixed-type AIHA is characterized by fewer clinical symptoms than cold agglutinin disease, hemolytic anemia is more severe and chronic. Therefore, it is important to confirm the presence of cold agglutinins, which are active at ≥30°C in patients with SLE and warm AIHA. In addition, it is important to consider that AIHA is associated with thromboembolism, and patients with lupus anticoagulant or anticardiolipin antibodies having a history of AIHA are at a high risk of developing thrombosis.

Study on the Preparation Method of Quality-Assured In-Hospital Drug Formulation for Children-A Multi-Institutional Collaborative Study.

The quality-assured preparation of crushed and diluted preparations for children is a challenge. In this study, a multicenter study was conducted to validate the preparation method for the quality assurance of baclofen powder, clonidine powder, and hydrocortisone powder prepared from tablets according to a previously established method. In-hospital preparations were prepared at five medical facilities under different crushing and mixing conditions. After storage in closed bottles, in-use bottles, and laminated paper for 120 days, ingredients stability, drug elution, and content uniformity after packaging were evaluated. All three ingredients were maintained at between 90% and 110% of their initial content for 120 days under packaging conditions of 25 ± 2 °C and 60 ± 5% relative humidity, with no change in dissolution in all formulations made at all five facilities. The content uniformity was also acceptable. The established method may contribute to quality-assured pediatric dosage form modification.

Drug Retention Rates and the Safety of Janus Kinase Inhibitors in Elderly Patients with Rheumatoid Arthritis.

BACKGROUND: We examined the real-world drug retention rate and safety data of Janus kinase inhibitors (JAKis) in elderly patients with rheumatoid arthritis (RA). METHODS: This study enrolled 133 RA patients (≥65 years) with sufficient clinical data who were initiated with JAKis during the study period. These patients were divided into two groups: the very elderly group (≥ 75 years) and the elderly group (65 ≤ years < 75). The drug retention rates of JAKis were compared using Kaplan-Meier curves. RESULTS: The discontinuation rates of JAKis were as follows: lack of effectiveness 27 (20.3%), adverse events (AEs) 29 (21.8%), and remission 2 (1.5%). There was no significant difference in the overall drug retention rate between the very elderly group (≥75 years) and the elderly group. Furthermore, the overall drug retention rates of JAKis were not affected by gender, methotrexate use, and anti-citrullinated protein/peptide antibody (ACPA) status. The discontinuation rates of JAKis due to AEs were comparable both in the very elderly group (≥75 years) and the elderly group (65 ≤ years < 75). Whereas chronic lung disease and hypoalbuminemia were independently associated with discontinuation rates due to AEs, the overall drug retention rates were significantly lower in patients treated with the approved dose of JAKis than in those treated with a reduced or tapered dose. CONCLUSIONS: Our results suggest that the overall drug retention rate of JAKis in very elderly patients (≥75 years) was comparable with that in elderly patients (65 ≤ years < 75). The discontinuation rates of JAKis due to AEs were also comparable both in very elderly group patients and elderly patients.

Drug Retention Rates of Janus Kinase Inhibitors in Rheumatoid Arthritis Patients with Therapy-Induced Lymphopenia.

OBJECTIVES: To determine whether drug-induced lymphocytopenia is associated with drug retention rates of JAKi (tofacitinib or baricitinib) in rheumatoid arthritis (RA) patients. METHODS: Patients with RA who were initiated with tofacitinib (n = 38) or baricitinib (n = 74) between July 2015 and July 2022 and continued for at least 4 months were enrolled in this study. Absolute lymphocyte count (ALC) value was obtained pre-treatment and monthly after initiation of JAKi (up to 4 months). Associations between ALC nadir at an early phase (up to 4 months) from JAKi initiation and drug retention rates were analysed. RESULTS: 112 patients (87 females; age, 71.2 ± 14.0 years; disease duration, 9.2 ± 10.5 months; DAS28-CRP, 3.60 ± 1.12; DAS28-ESR, 4.43 ± 1.29; CDAI, 17.9 ± 12.9; C-reactive protein, 3.07 ± 3.43 mg/dL; and lymphocyte count, 1361.9 ± 538.7 per µL) treated with tofacitinib or baricitinib were retrospectively analysed. Lymphocytopenia (>10% decline in lymphocyte count to pre-treatment basal levels) was observed in a quarter of RA patients treated with JAKi (tofacitinib; 16 baricitinib; 14). RA patients with lymphopenia were associated with the lower drug retention rates of tofacitinib compared to those without lymphocytopenia. The reduced drug retention rates in patients with lymphocytopenia were attributed to the discontinuation of tofacitinib due to AEs. Whereas lymphocytopenia was not associated with lower drug retention rates of baricitinib. Pre-treatment absolute lymphocyte counts did not affect the drug retention rates of JAKi in patients with RA. CONCLUSIONS: These findings suggest that lymphopenia during the first 4 months from the initiation of JAKi is associated with reduced drug retention rates in patients with RA due to AEs, which is exclusively associated with the use of tofacitinib.

Evolutionary histories of breast cancer and related clones.

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.

[Mood Stabilizers: An Overview].

Bipolar disorder, a mental illness that affects mood, behavior, and motivation is characterized by alternating depressive and manic (hypomanic) episodes (some mixed episodes include both types of symptoms), with periods of remission between episodes. Symptoms and progress vary across patients. Treatment includes anti-seizure medications and maintenance therapy to prevent seizures. Classically, lithium carbonate and valproate are the most commonly used medications; however, in addition to lamotrigine, atypical antipsychotics including aripiprazole, quetiapine, and lurasidone are being used in recent years. Theoretically, patients are administered monotherapy; however, it is not uncommon to use combination treatment in clinical practice.

Case report: Rapid development of amyloid A amyloidosis in temporal arteritis with SAA1.3 allele; An unusual case of intestinal amyloidosis secondary to temporal arteritis.

Temporal arteritis (TA) is a large-vessel vasculitis mostly seen in older patients. Amyloid A (AA) amyloidosis secondary to a chronic inflammation induces multiple organ dysfunctions, including a dysfunction of the gastrointestinal tract. Herein, we present a case of TA complicated by AA amyloidosis that was resistant to oral and intravenous steroids. An 80-year-old man with a history of new-onset headache, jaw claudication, and distended temporal arteries was referred to our department. On admission, the patient presented with tenderness and a subcutaneous temporal nodule in both temple arteries. Ultrasonography of the nodule revealed an anechoic perivascular halo surrounding the right temporal artery. Following the diagnosis of TA, high-dose prednisolone therapy was initiated. However, the patient presented with recurrent abdominal pain and refractory diarrhea. Due to the unclear origin of refractory diarrhea, an extensive workup, including biopsy of the duodenal mucosa, was performed. Endoscopy revealed chronic inflammation in the duodenum. Immunohistochemical analysis of duodenal mucosal biopsy samples revealed AA amyloid deposition resulting in the diagnosis of AA amyloidosis. After tocilizumab (TCZ) administration, refractory diarrhea reduced; however, the patient died of intestinal perforation 1 month after the start of TCZ administration. Gastrointestinal involvement was the main clinical manifestation of AA amyloidosis in the present case. This case highlights the importance of bowel biopsy screening for amyloid deposition in patients with unexplained gastrointestinal tract symptoms, even in a recent onset of large-vessel vasculitis. In the present case, the carriage of the SAA1.3 allele likely contributed to the rare association of AA amyloidosis with TA.

Clinical Features and Outcomes of Japanese Patients with Giant Cell Arteritis: A Comparison with Takayasu Arteritis.

BACKGROUND: Giant cell arteritis (GCA) and Takayasu arteritis (TA) are distinct types of large-vessel vasculitis; however, the clinical features of the diseases have some similarities. Limited data are available regarding Japanese patients with GCA and TA. The present study aimed to compare the clinical features and outcomes of Japanese patients with GCA and TA and the effects of large vessel involvement (LVI). METHODS: We performed a retrospective cohort study of the patients with GCA (n = 15) and TA (n = 30) who visited our department from April 2012 to June 2022. Signs and symptoms attributed to the disease, treatment, clinical outcomes, and mortality were recorded using a standardized database. RESULTS: The median age of onset was significantly higher in the GCA group at 24 years (range, 16-72 years) in the TA group and 77 years (range, 57-89 years) in the GCA group (p < 0.001). There were no significant differences in survival rates or the cumulative rates of cardiovascular events between the GCA and TA groups. However, relapse-free survival rates were significantly higher in patients with GCA than in patients with TA. Seven of the 15 patients with GCA had large vessel involvement, which did not affect the survival rates. Prednisolone (PSL) doses were significantly decreased after induction therapy in both groups, and the rates of achieving steroid tapering (PSL < 5.0 mg/day) were significantly higher in patients with GCA compared with those in patients with TA. CONCLUSIONS: Our study demonstrated no significant difference in the survival rates of Japanese patients with GCA and TA. The relapse-free survival rates were significantly higher in the GCA group than in the TA group. LVI may not be associated with disease relapse or survival rate in Japanese patients with GCA.