Alpha Inhibitors Research Articles

Prevalence of metabolic syndrome and chronic inflammation in psoriasis before and after biologic therapy: a prospective study.

As a chronic inflammatory disease, psoriasis affects not only the skin but also the metabolic profile of the patients. Biologic therapies, including tumor necrosis alpha (TNF-a) inhibitors and interleukin (IL)-12/23 and IL-17 antagonists, have proven effective in the reduction of psoriasis severity; however their impact on the metabolic and chronic inflammatory profiles of the patients remains incompletely elucidated. We performed a longitudinal case-control study on 106 psoriasis patients and an equal number of controls without the disease, as well as a prospective study on the patient group with the end point being 6 months of biologic therapy. Patients received either ixekizumab, secukinumab, guselkumab, certolizumab, ustekinumab, risankizumab, or adalimumab. Abdominal circumference, serum fasting glucose, triglycerides (TG), high-density lipoproteins (HDL), erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) were measured for both patients and controls, with an additional measurement for patients after 6 months. At baseline, the number of psoriasis patients suffering from obesity, metabolic syndrome, and chronic inflammation significantly outnumbered controls (p<0.05), with the calculated odds ratio being 1.88, 6.83, and 81.84 for these conditions in psoriasis, respectively. Biologic therapies increased the abdominal circumference of patients in a slight but significant fashion (p<0.05), as well as significantly improved HDL, CRP, ESR levels at 6 months (p<0.05). Moreover, after 6 months, the number of patients meeting the diagnostic criteria for metabolic syndrome and chronic inflammation was significantly lower than at baseline (p<0.001). According to our results, biologic therapies improve the overall metabolic and inflammatory profiles of psoriasis patients, the most significant ameliorations being noticed for serum HDL, CRP, and ESR.

Predictors of functional and morphological arterial wall properties in coronary artery disease patients with increased lipoprotein (a) levels before and after treatment with proprotein convertase subtilisin-kexin type 9 inhibitors

BackgroundIn addition to proatherogenic properties, lipoprotein (a) (Lp(a)) has also pro-inflammatory, antifibrinolytic and prothrombogenic features. The aim of the current study was to identify the predictors of functional and morphological properties of the arterial wall in patients after myocardial infarction and increased Lp(a) levels at the beginning and after treatment with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors.MethodsSeventy-six post-myocardial infarction patients with high Lp(a) levels were included in the study. Ultrasound measurements of flow-mediated dilation of brachial artery (FMD), carotid intima-media thickness (c-IMT) and pulse wave velocity (PWV) were performed initially and after 6 months of treatment. At the same time points lipids, Lp(a), inflammatory and hemostasis markers were measured in blood samples.ResultsIn linear regression model FMD significantly correlated with age at first myocardial infarction (β = 0.689; p = 0.022), high-sensitivity C-reactive protein (β = -1.200; p = 0.009), vascular cell adhesion protein 1 (VCAM-1) (β = -0.992; p = 0.006), overall coagulation potential (β = 1.428; p = 0.014) and overall hemostasis potential (β = -1.473; p = 0.008). c-IMT significantly correlated with age at first myocardial infarction (β = 0.574; p = 0.033) and Lp(a) (β = 0.524; p = 0.040). PWV significantly correlated with systolic blood pressure (β = 0.332; p = 0.002), tumor necrosis factor alpha (β = 0.406; p = 0.002), interleukin-8 (β = -0.315; p = 0.015) and plasminogen activator inhibitor 1 (β = 0.229; p = 0.031). After treatment FMD reached statistical significance only in univariant analysis with systolic blood pressure (r = -0.286; p = 0.004) and VCAM-1 (r = -0.229; p = 0.024). PWV and c-IMT correlated with age (r = 0.334; p = 0.001 and r = 0.486; p < 0.0001, respectively) and systolic blood pressure (r = 0.556; p < 0.0001 and r = 0.233; p = 0.021, respectively).ConclusionsOur results suggest that age, systolic blood pressure, Lp(a) levels and other biochemical markers associated with Lp(a) are predictors of functional and morphological properties of the arterial vessel wall in post-myocardial patients with high Lp(a) levels initially. However, after 6 months of treatment with PCSK9 inhibitors only age and systolic blood pressure seem to be predictors of these properties.Trial registrationThe protocol for this study was registered with clinicaltrials.gov on November, 3 2020 under registration number NCT04613167.Graphical

In silico screening of potential Tumor necrosis factor alpha (TNF-α) inhibitors through molecular modeling, molecular docking, and pharmacokinetics evaluations

The multifunctional cytokine TNF-α serves as a key biological mediator for several important immune processes, such as inflammation, infection, and antitumor responses. It is crucial for both acute and chronic neuroinflammation, as well as several neurodegenerative diseases. For the treatment of inflammatory diseases, the synthetic antibodies etanercept, adalimumab, and the generic medication Diclophenac directly bind to TNF-α, preventing it from interacting with the tumor necrosis factor receptor (TNFR). These approved drugs have detrimental side effects. There is therefore a lot of interest in the scientific world to identify new small-molecule-based TNF-α inhibition therapies. In this study, a set of molecular modeling techniques have been applied including the QSAR model, docking, and pharmacokinetics prediction to identify and optimize novel TNF-α inhibitors. Based on the modeling techniques applied, the QSAR shows (R2= 0.9534, Q2 = 0.8707, Rpred2= 0.8599, cRr2= 0.8994, SEE = 0.1067). The results showed that the function of these discovered compounds was not connected to lipophilicity, whereas less lengthy NN bonds and long substituents might lead to quite bioactive molecules. The discovered hits indicate promising inhibition against TNF-α and lacked harmful effects. Most of the discovered molecules had higher TNF-binding affinity than the reference substance. Furthermore, comparing the reference drug grading (ds) of 0.38, molecule 74 with PubChem ID 2998055 exhibits superior properties with a drug grading (ds) of 0.76. As a whole, the discovered molecules have favorable pharmacokinetics, pharmacodynamics, and drug interaction properties that suggest promising TNF- inhibition and lacked toxicity, suggesting that they are potential drug candidates.

Platelet-rich fibrin therapy as an adjuvant treatment in the management of metastatic Crohn’s disease: A case series

Abstract Metastatic or cutaneous Crohn’s disease (MCD) is a rare manifestation of Crohn’s disease and presents with ulcers, nodules, edema, fissures, and fistula. The genital involvement is seen in almost 50% patients and linear ulcers (knife-cut ulcers) are characteristic clinical features. The histopathological findings of skin lesions are similar to gastrointestinal involvement and is diagnostic. The treatment options for the management of MCD include topical and oral steroids, oral metronidazole, as well as immunosuppressants such as methotrexate, azathioprine, cyclosporine, and tumor necrosis factor alpha inhibitors. We present three cases of MCD who were treated with platelet-rich fibrin therapy as adjuvant and resulted in rapid healing of ulcers.

MATH: A Deep Learning Approach in QSAR for Estrogen Receptor Alpha Inhibitors.

Breast cancer ranks as the second leading cause of death among women, but early screening and self-awareness can help prevent it. Hormone therapy drugs that target estrogen levels offer potential treatments. However, conventional drug discovery entails extensive, costly processes. This study presents a framework for analyzing the quantitative structure-activity relationship (QSAR) of estrogen receptor alpha inhibitors. Our approach utilizes supervised learning, integrating self-attention Transformer and molecular graph information, to predict estrogen receptor alpha inhibitors. We established five classification models for predicting these inhibitors in breast cancer. Among these models, our proposed MATH model achieved remarkable precision, recall, F1 score, and specificity, with values of 0.952, 0.972, 0.960, and 0.922, respectively, alongside an ROC AUC of 0.977. MATH exhibited robust performance, suggesting its potential to assist pharmaceutical and health researchers in identifying candidate compounds for estrogen alpha inhibitors and guiding drug discovery pathways.

COVID-19 in Patients with Systemic Inflammatory Diseases: Impact on Disease Activity.

COVID-19 pandemic, an international emergency, raised concerns about the interaction of this infection and disease-modifying drugs used in the treatment of Systemic inflammatory diseases (SID). Understanding the relationship between COVID-19 and disease activity is crucial to adapt the treatment. The aim of our study was to determine the impact of COVID-19 on the disease activity of rheumatic diseases. We performed a cross-sectional study, including patients with SID (rheumatoid arthritis (RA) and spondyloarthritis (SpA)). Disease activity was evaluated during the last check-up before COVID-19 and within the period of 6 months after the infection. Activity scores were assessed with Disease Activity Score (DAS28) for RA and Ankylosing Spondylitis Disease Activity Score (ASDAS) for SpA. Correlation and regression coefficients were used to evaluate associations among the variables. Totally, thirty-two patients were included; twenty followed for RA and twelve for axial SpA. The mean disease duration of the underlying rheumatic disease was 10.2 years (2-30). RA was seropositive and erosive in 61% and 31%, respectively. Seventeen patients were on csDMARDs: 14 were on Methotrexate and three patients were on Salazopyrine. Ten patients (31%) were treated with bDMARDs; Tumor necrosis factor (TNF)-alpha inhibitors were used in eight cases. Rituximab and secukinumab were prescribed for one patient each. In 70%, COVID-19 was pauci-symptomatic. A severe form with a need for hospitalization was noted in 9%. Two patients were admitted to the intensive care unit (ICU). Overall, treatment with DMARDs was interrupted in all cases: when COVID-19 symptoms began in 82% and when PCR was positive in 18%. Both RA and axial SpA were not active after a mean period of 6 months after COVID-19 infection (p = 0.818 and p = 0.626, respectively). Although our patients interrupted their DMARDs, our study demonstrates that disease activity as assessed by ASDAS and DAS28 in SpA and RA remained unchanged after COVID-19.

Regulatory T Cell-Targeted Immunomodulatory Therapy for Long-Term Clinical Improvement of Atopic Dermatitis: Hypotheses and Perspectives.

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disorder characterized by itching and eczematous lesions. It is often associated with a personal or familial history of allergic diseases. Allergic inflammation induced by immunoglobulin E and T-helper type 2 (Th2) cell responses to common environmental agents has been suggested to play an essential role in AD pathogenesis. The standard therapies for AD, including topical or systemic agents, focus on controlling skin inflammation. Recently developed monoclonal antibody to interleukin-4 receptor alpha or Janus kinase inhibitors can provide significant clinical improvements in patients with AD by inhibiting Th2 cell-mediated skin inflammation. However, the clinical efficacy of the Th2 cell-targeted therapy is transient and incomplete in patients with AD. Patients with AD are seeking a permanent cure. Therefore, the development of novel immunomodulatory strategies that can improve a long-term clinical outcome and provide a long-term treatment-free clinical remission of AD (disease-modifying therapy) is needed. Regulatory T (Treg) cells play a critical role in the maintenance of immune tolerance and suppress the development of autoimmune and allergic diseases. This review provides three working hypotheses and perspectives for the treatment of AD by Treg cell activation. (1) A decreased number or function of Treg cells is a critical event that causes the activation of Th2 cells, leading to the development and maintenance of AD. (2) Activation of Treg cells is an effective therapeutic approach for AD. (3) Many different immunomodulatory strategies activating Treg cells can provide a long-term clinical improvement of AD by induction of immune tolerance. The Treg cell-targeted immunomodulatory therapies for AD include allergen immunotherapy, microbiota, vitamin D, polyvalent human immunoglobulin G, monoclonal antibodies to the surface antigens of T cell or antigen-presenting cell, and adoptive transfer of autologous Treg cells or genetically engineered Treg cells expanded in vitro.

Maternal and neonatal antibody levels on pertussis vaccination in pregnant women on immune-modulating therapy for rheumatic disease

ObjectivesWhile protection against pertussis following maternal tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccination was demonstrated in healthy term-born infants, no evidence is available on Tdap vaccination in combination with immune-modulating therapy during pregnancy. In...

Extraction optimization and constituent analysis of total flavonoid from Hosta plantaginea (Lam.) Aschers flowers and its ameliorative effect on chronic prostatitis via inhibition of multiple inflammatory pathways in rats

Ethnopharmacological relevanceHosta plantaginea (Lam.) Aschers flowers (HPF) are well-known for their high flavonoid content, which contribute to their widely as traditional Chinese medicine for alleviating inflammation. Despite their recognized potential, information regarding the total flavonoid (TF) of HPF and its therapeutic application in treating chronic prostatitis (CP) remains unknown. Aim of the studyWe aimed to investigate the extraction optimization, constituent analysis, and alleviating effect of TF on CP as well as its potential mechanism. Materials and methodsThe optimized extraction of TF from HPF was explored using response surface methodology with a Box-Behnken design model. The major flavonoids in TF were identified based on UHPLC-MS approach. Efficacy of TF (25 and 100 mg/kg, p.o.) on CP was evaluated in prostate antigen emulsion-induced autoimmune CP rat model by measuring prostatic index, the levels of leukocytes and lecithin bodies, as well as histopathological examination. The protein expression contents were detected by western blotting. Additionally, the antioxidant (DPPH and ABTS) and anti-inflammatory (cyclooxygenase 2, COX-2 inhibitory) effects of TF were also evaluated in vitro. ResultsThe optimized conditions for TF extraction were determined as 60% ethanol concentration, 30 mL/g liquid-to-solid ratio, 30 min extraction time, and 90 °C extraction temperature, and the extraction ratio is 65.98 ± 2.14%. A total of 15 major flavonoids in TF were characterized by comparison with reference standards. TF ameliorated the efficacy of CP in rats in a dose-independent manner, including reduced prostatic index and leukocytes levels, elevated lecithin body levels, ameliorated histopathological damage to prostate, and suppressed phosphorylated protein expressions of nuclear factor kappa-B (NF-κB) p65, inhibitor of NF-κB alpha (IκBα), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (Erk), just another kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt). Simultaneously, the IC50 of TF to DPPH, ABTS radicals, and COX-2 were 2.02, 1.79, and 0.0838 mg/mL, respectively. ConclusionsWe first demonstrated that TF from HPF represents a promising candidate to alleviate CP through suppression of NF-κB, MAPKs, JAK-STAT, and PI3K-Akt signaling pathways.

Therapeutic effect of Hosta plantaginea (Lam.) Aschers flowers on acute pharyngitis through inhibition of multi-inflammatory pathways in rats

BackgroundHosta plantaginea (Lam.) Aschers flower is a famous Mongolian folk medicine in China and has a therapeutic effect on acute pharyngitis (AP). However, the effect and potential mechanism of H. plantaginea flower on AP have not been fully elucidated. Aim of the studyThe present work aimed to evaluate the effects and mechanisms of the crude extract of H. plantaginea flowers (HP) and its four fractions of petroleum ether fraction (HPA), ethyl acetate fraction (HPB), n-butanol fraction (HPC), and water residue (HPD) against AP in rats. Materials and methodsA 15% ammonia-induced AP rat model in rats was established. Therapeutic effects of HP and HPA∼D in model rats were evaluated based on body weight, histopathological analysis, and inflammatory parameters, including tumor necrosis factor α (TNF-α), prostaglandin E2 (PGE2), interleukin 1β (IL-1β), and IL-6. The protein expression of nuclear factor kappa-B p65 (NF-κB p65), inhibitor of NF-κB alpha (IκBα), c-Jun N-terminal kinases (JNK), mitogen-activated protein kinase (MAPK) p38, extracellular signal-regulated kinase (Erk), just another kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt) were detected by a Western blotting assay. ResultsHP, HPB, and HPC treatments markedly alleviated AP in rats by increasing body weight and improving pathological damages in pharyngeal tissues. In addition, HP, HPB, and HPC treatments significantly inhibited inflammation, including decreasing the levels of TNF-α, PGE2, IL-1β, and IL-6, and suppressing phosphorylated protein expression of p65, IκBα, JNK, p38, Erk, JAK1, STAT3, PI3K, and Akt in pharyngeal tissues of rats. ConclusionCollectively, HP, HPB, and HPC can attenuate pharynx injury in rats by suppressing inflammation via inhibition of NF-κB, MAPKs, JAK-STAT, and PI3K-Akt pathways, which supports the traditional use of H. plantaginea flowers.

Current and Emerging Therapies for Chronic Spontaneous Urticaria: A Narrative Review.

Chronic spontaneous urticaria (CSU) is a condition in which wheals, angioedema, and pruritus occur spontaneously and recurrently for at least 6weeks. The etiology of this disease is partially dependent on production of autoantibodies that activate and recruit inflammatory cells. Although the wheals can resolve within 24h, symptoms have a significant detrimental impact on the quality of life of these patients. Standard therapy for CSU includes second-generation antihistamines and omalizumab. However, many patients tend to be refractory to these therapies. Available treatments such as cyclosporine, dapsone, dupilumab, and tumor necrosis factor alpha (TNFa) inhibitors have been used with success in some cases. Furthermore, various biologics and other novel drugs have emerged as potential treatments for this condition, and many more are currently under investigation in randomized clinical trials.

Conquering pyoderma gangrenosum: exploring non-steroidal treatment options

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis frequently related to chronic inflammatory bowel disease (IBD) and often associated with exacerbation of intestinal disease and/or loss of treatment efficacy. The mainstay of treatment is long-term immunosuppression, often with high doses of corticosteroids or low doses of ciclosporin. PG has been reported to respond to TNF alpha inhibitors. We report a patient of recalcitrant PG who responded very well to treatment with golimumab. A 61-year-old known case of PG since 4 years, who also had history of hypertension, pulmonary TB (treated), had been treated with dapsone, thalidomide, colchicine and corticosteroids in the past with partial response and frequent relapses. In February 2021, the patient while being on low-dose oral corticosteroids and colchicine, presented with large painful ulcer over back of his right thigh, which rapidly worsened. In agreement with the pulmonologist, the patient was started on Injection golimumab in addition to intravenous dexamethasone with slow tapering of steroid dosage following the improvement of the cutaneous lesion. Patient reported a near-total resolution of lesion after two doses. He is maintaining well with golimumab. PG can be poorly responsive despite adequate treatment with conventional modalities. High dose steroid therapy with all expected iatrogenic complications and treatment with cyclosporine in such an elderly patient with hypertension and history of tuberculosis seemed to be inappropriate. For all these reasons, a treatment with the TNF alpha inhibitor golimumab, appeared to be the most reasonable therapeutic choice for a patient.

A case of perifolliculitis capitis abscedens et suffodiens and acne conglobata effectively treated with a tumor necrosis factor α inhibitor.

Perifolliculitis capitis abscedens et suffodiens (PCAS) and acne conglobate (AC) are often treated with isotretinoin and tumor necrosis factor alpha (TNF-α) inhibitors in Europe and the United States. Treatment with these drugs is uncommon in Asia, and alternative treatment options are limited. In this paper, we report the case of a Japanese patient who presented with PCAS and AC and was treated successfully with adalimumab.

Comparison of time of onset of leukemia with patients receiving adalimumab vs other TNF α inhibitors.

e19034 Background: TNF α (Tumor necrosis factor alpha) inhibitors were first approved by US FDA (Food and drug administration) in the late 1990s to manage several inflammatory conditions. Theoretically, TNF α inhibitors have an elevated risk of malignancies as TNF plays a role in cell apoptosis. The development of newer human monoclonal TNF α antibodies like Adalimumab has been approved for a broader clinical spectrum of activity. However, any increase relative risk of malignancies associated with these drugs is highly debatable, with many post-marketing surveillance studies showing no significant increases in the relative risk of malignancies receiving these drugs. We hypothesize with the null hypothesis stating that there is no significant difference in the time of onset of acute leukemia in the patients receiving Adalimumab in comparison with other TNF α inhibitors. Methods: A comprehensive literature search of PubMed, Embase, and Cochrane was conducted. A total of 19 cases of acute leukemia were reported in association with TNF α inhibitors receiving it for various inflammatory conditions. Of nineteen patients, ten received Adalimumab as the last TNF α inhibitor, while nine received other TNF α inhibitors for various inflammatory etiologies. These patients received multiple lines of treatment with steroids, Thiopurines, Methotrexate, and TNF α inhibitors with varying duration of disease activity. We performed a one-way ANOVA analysis comparing the mean duration of the last TNF inhibitor with the time to diagnosis of leukemia. Results: The results indicate a significant effect [F (1, 17) = 5.652, p=0.029 &lt; 0.05]. The comparison revealed a significant difference between the patients who took Adalimumab (M=5.650; SD=3.8733) and other TNF α inhibitors (M=23.333; SD=23.2379) as the last drug. We, therefore, reject the null hypothesis as there is a significant difference in the time of onset of acute leukemia in the patients receiving Adalimumab in comparison with other TNF α inhibitors. Conclusions: In this limited study of the cases of acute leukemia reported in the literature receiving TNF inhibitors for various inflammatory conditions, patients receiving Adalimumab would have the early time of onset of leukemia in comparison with the other TNF α inhibitors. [Table: see text]

Early efficacy evaluation of ORIN1001, a first in class IRE1 alpha inhibitor, in advanced solid tumors.

1092 Background: ORIN1001 is a first-in-class small molecule targeting a novel enzyme with a unique mode of inhibition that selectively blocks the Inositol Requiring Enzyme 1α (IRE1) RNAse and blocks X-Box Binding Protein 1 (XBP1) activation in the endoplasmic reticulum. ORIN1001 is now undergoing Phase 1/2 clinical testing in advanced solid tumors. Methods: In a Phase 1 dose escalation trial (3+3 design), ORIN1001 was administered PO daily as a single agent in patients (pts) with advanced solid tumors and in combination with Abraxane in pts with relapsed, refractory breast cancer. Safety, tolerability, pharmacokinetics, and preliminary efficacy of ORIN1001 was evaluated and a RP2D determined. Results: As of Jan, 2023, 30 patients with advanced cancer have received ORIN1001 as a single agent at doses up to 650 mg per day in 21-day continuous cycles and 13 patients with breast cancer have received ORIN1001 at doses up to 400 mg in combination with Abraxane in 28-day continuous cycles. For single agent, DLTs consisting of thrombocytopenia were observed at 200 mg (2 pts) and 650 mg (2 pts) and, rash was observed at 200 mg (1 pt) and 500 mg (1 pt). For combination treatment, DLTs consisting of thrombocytopenia were observed at 300 mg (1 pt), fatigue/ rash at 400 mg (1 pt), febrile neutropenia/low WBC at 400/500 mg (1 pt at each dose). Common ( &gt; 15%) adverse events were predominantly nausea and/or vomiting (Grade 1-2 in severity). ORIN1001 exposure increased in a dose proportional manner with a mean T1/2 at steady state of approximately 20 hours. For single agent, best response per RECIST 1.1 was partial response (PR) in 2 of 30 pts. These PRs included a stage IV colon cancer pt exceeding 44 months on treatment at 100 mg, and stage IV ER-/PR-/HER2+ breast cancer pt with 5 months on treatment at 500 mg. Stable disease (SD) was observed in a total of 16 of 30 pts with breast, colorectal, mesothelioma, liver, prostate, kidney or ovarian cancer. For combination therapy with Abraxane, a PR was observed in one ER+/PR-/HER2- breast cancer pt at 300 mg ORIN1001 and SD was observed in 5 of 13 pts. SD included both triple negative and ER+/HER2- breast cancer pts at 300 or 400 mg with ongoing treatment exceeding 5 months. Of note, in a separate Phase 1 oncology basket trial in China, there were 2 PRs; 1 pt with stage IV NSCLC at 300 mg and 1 pt with metastatic castrate resistant prostate cancer at 100 mg exceeding 9 and 5 months of treatment with ORIN1001 in combination with Abraxane, respectively. Conclusions: Phase 1 clinical evaluation of ORIN1001 has demonstrated tolerability and dose proportional PK. The proposed RP2D is estimated to be 500 mg and 300 mg ORIN1001 for single agent and in combination with Abraxane, respectively. Early efficacy data with ORIN1001 demonstrate clinical responses (SD and PR) in multiple pts with heavily-pretreated advanced solid tumors as a single agent or in combination with Abraxane in breast cancer patients. Clinical trial information: NCT03950570 .

Drug Survival of Tumor Necrosis Factor-Alpha Inhibitors and Switched Subsequent Biologic Agents in Patients with Psoriasis: A Retrospective Study.

This study aimed to retrospectively examine the drug survival of tumor necrosis factor (TNF)-alpha inhibitors and switched subsequent biologic agents after discontinuation of TNF inhibitors. This real-world setting study was conducted at a single academic center. We included patients who were treated with adalimumab (n = 111), certolizumab pegol (n = 12), and infliximab (n = 74) at Jichi Medical University Hospital from 1 January 2010 to 31 July 2021. No significant differences were noted in drug survival between the three TNF inhibitors. The 10-year drug survival rate for adalimumab and infliximab was 14% and 18%, respectively. Of the patients who discontinued TNF inhibitors for any reason (n = 137), 105 chose biologics as their subsequent treatment. The subsequent biologics included 31 cases of TNF inhibitors (adalimumab in 20, certolizumab pegol in 1, and infliximab in 10), 19 of interleukin-12/23 inhibitor (ustekinumab), 42 of interleukin-17 inhibitors (secukinumab in 19, brodalumab in 9, and ixekizumab in 14) and 13 of interleukin-23 inhibitors (guselkumab in 11, risankizumab in 1, and tildrakizumab in 1). Cox proportional hazards analysis for the subsequent drugs in cases of discontinuation due to inadequate efficacy revealed that female sex was a predictor of drug discontinuation (hazard ratio 2.58, 95% confidence interval 1.17-5.70) and that taking interleukin-17 inhibitors rather than TNF inhibitors was a predictor of drug persistence (hazard ratio 0.37, 95% confidence interval 0.15-0.93). Interleukin-17 inhibitors may be a favorable option for patients who need to switch from TNF inhibitors due to inadequate efficacy. However, this study is limited by the small number of cases and its retrospective design.

Post-traumatic ulcerated and chronic necrobiosis lipoidica of the elbow: A new entity?

BackgroundNecrobiosis lipoidica (NL) is a chronic granulomatous dermatosis usually affecting the lower limbs, although less common sites have been described. Herein we report a series of cases of NL located on the elbow, with an unusual presentation and occurring after trauma or surgery. ObservationsOur series includes three men and one woman, with a mean age of 64 years. Three had undergone surgery for elbow bursitis and one had had trauma after a fall from a horse, with exposure of subcutaneous tissue prior to healing. Within 5 years, they had all developed an atrophic erythematous annular plaque with papular and telangiectatic edges, with recurrent episodes of ulceration and scarring. Repeated tests for infectious agents were negative. Histological examinations showed granulomas and necrobiosis with palisading or early-stage palisading. Partial healing was achieved in two patients after 6 months of doxycycline. Treatment with adalimumab resulted in disappearance of the ulcers at 6 months in one patient. DiscussionUnusual sites of NL impose consideration of other types of palisading granuloma or mycobacterial infections, which we were able to rule out. Two other cases of NL of the elbow similar to ours are reported in the literature. These cases, involving multiple ulcerations over a very long period of time, probably constitute a distinct entity because of the very distinct character of these 6 cases. Tetracyclines are partially active and tumour necrosis factor alpha (TNF)-alpha inhibitors may offer an option.

Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells.

Pulmonary arterial hypertension (PAH) is a pathophysiological state of abnormally elevated pulmonary arterial pressure caused by drugs, inflammation, toxins, viruses, hypoxia, and other risk factors. We studied the therapeutic effect and target of tetramethylpyrazine (tetramethylpyrazine [TMP]; ligustrazine) in the treatment of PAH and we speculated that dramatic changes in myocardin levels can significantly affect the progression of PAH. In vivo, the results showed that administration of TMP significantly prolonged the survival of PAH rats by reducing the proliferative lesions, right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), and the Fulton index in the heart and lung of PAH rats. In vitro, TMP can regulate the levels of smooth muscle protein 22-alpha (SM22-α), and myocardin as well as intracellular cytokines such as NO, transforming growth factor beta (TGF-β), and connective tissue growth factor (CTGF) in a dose-dependent manner (25, 50, or 100 μM). Transfection of myocardin small interfering RNA (siRNA) aggravated the proliferation of pulmonary artery smooth muscle cells (PSMCs), and the regulatory effect of TMP on α-smooth muscle actin (α-SMA) and osteopontin (OPN) disappeared. The application of 10 nM estrogen receptor alpha (ERα) inhibitor MPP promoted the proliferation of PSMCs, but it does not affect the inhibition of TMP on PSMCs proliferation. Finally, we found that TMP promoted the nucleation of myocardin-related transcription factor-A (MRTF-A) and combined it with myocardin. In conclusion, TMP can inhibit the transformation of PSMCs from the contractile phenotype to the proliferative phenotype by promoting the formation of the nuclear (MRTF-A/myocardin) transcription complex to treat PAH.

Safety and Effectiveness of Vedolizumab in Patients with Moderate-to-Severe Ulcerative Colitis: An Interim Analysis of a Japanese Post-Marketing Surveillance Study.

This ongoing post-marketing surveillance monitors the long-term safety and effectiveness of vedolizumab in routine clinical practice in patients with moderate-to-severe ulcerative colitis (UC) in Japan. This interim analysis assessed induction-phase data, covering the initial three doses of vedolizumab. Patients were enrolled via a web-based electronic data capture system from approximately 250 institutions. Incidence of adverse events and treatment responses were assessed by the physicians after the patient had received three doses of vedolizumab or when the drug was discontinued, whichever occurred first. Therapeutic response was defined as any treatment response, including remission or improvement of complete or partial Mayo score, and was assessed in the total and stratified patient populations according to prior tumor necrosis factor alpha (TNFα) inhibitor treatments and/or baseline partial Mayo score. The total incidence of adverse drug reactions (ADRs) was 4.10% (11/268). Common ADRs were dizziness, nausea, and arthralgia, each reported in 0.75% of patients (2/268). Serious ADRs were herpes zoster oticus and UC, each reported in 0.37% of patients (1/268). Therapeutic response was reported in 84.5% (218/258) of all patients, 85.8% (127/148) of TNFα inhibitor-naïve patients, and 82.7% (91/110) of TNFα inhibitor-experienced patients. Among patients with partial Mayo score of ≥ 4 at baseline, partial Mayo score remission in patients without or with prior TNFα inhibitor treatment was 62.5% (60/96) and 45.6% (36/79), respectively. The results confirm a safety and effectiveness profile of vedolizumab consistent with that observed in previous trials. JapicCTI-194603, NCT03824561.

CircSLC8A1 targets miR-181a-5p/HIF1AN pathway to inhibit the growth, migration and extracellular matrix deposition of human keloid fibroblasts.

Circular RNAs (circRNAs) are identified as important regulators in human diseases, including keloid. The purpose of this study is to reveal the role and molecular mechanism of circSLC8A1 in keloid formation. Expression of circSLC8A1, microRNA (miR)-181a-5p, and hypoxia inducible factor 1 alpha inhibitor (HIF1AN) were detected by quantitative real-time PCR. Protein expression of extracellular matrix (ECM) deposition markers and HIF1AN was detected by western blot analysis. Furthermore, the interaction between miR-181a-5p and circSLC8A1 or HIF1AN was confirmed by dual-luciferase reporter assay, RIP assay and RNA pull-down assay. Expression of circSLC8A1 was downregulated in keloid tissues and HKFs. Overexpression of circSLC8A1 suppressed HKFs proliferation, migration, ECM deposition, and promoted apoptosis. MiR-181a-5p is targeted by circSLC8A1, and its mimic reversed the effect of circSLC8A1 on the biological function of HKFs. HIF1AN was a target of miR-181a-5p, and it was positively regulated by circSLC8A1. Knockdown of HIF1AN also reversed the negatively regulation of circSLC8A1 on the biological functions of HKFs. Our data showed that circSLC8A1 regulates the miR-181a-5p/HIF1AN axis to restrain HKFs biological functions, confirming that circSLC8A1 might serve as a novel therapeutic target for keloids.