Tumor Necrosis Factor Alpha Inhibitors Research Articles

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.

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...

Paradoxical Tumor Necrosis Factor-Alpha (TNF-α) Inhibitor-Induced Psoriasis: A Systematic Review of Pathogenesis, Clinical Presentation, and Treatment.

Tumor necrosis factor-alpha (TNF-α) inhibitors have been shown to be well tolerated among patients with rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Meanwhile, more recently, clinical practice and research efforts have uncovered increasing cases of psoriatic lesion development tied to initiating treatment with a TNF-α inhibitor. The underlying mechanisms associated with this occurrence have yet to be fully elucidated. A review and analysis of cases of paradoxical psoriasis currently published in the literature is warranted. In addition, exploring possible mechanisms of action and potential treatment options associated with favorable outcomes is much needed. A systematic literature review was performed utilizing PubMed and Google Scholar databases (1992-present), in which 106 cases of paradoxical psoriasis were reviewed. The most common morphology developed was plaque psoriasis vulgaris. There was a female predominance (61.3%), and the most common underlying autoimmune disease was rheumatoid arthritis (45.3%). In addition, the most commonly associated drug with the onset of psoriatic lesions was infliximab (62.3%). Furthermore, the findings suggest that the most well-supported mechanism of action involves the uncontrolled release of interferon-alpha (IFN-α) from plasmacytoid dendritic cells (pDCs) after TNF-α inhibition. While TNF-α inhibitors have been shown to have great benefits to patients with rheumatologic diseases, cases of paradoxical psoriasis demonstrate the importance of close monitoring of patients on TNF-α inhibitors to allow for early recognition, treatment, and potentially change to a different mechanism of action of the medication used to prevent further progression of the inflammatory lesions.

COVID-19 outcomes in patients with rheumatoid arthritis with biologic or targeted synthetic DMARDs

ObjectivesWe aimed to investigate the role of rheumatoid arthritis (RA) with biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD) exposure in COVID-19 outcomes.MethodsOur study retrieved data from the US Collaborative...

Insight Of Engineered Nano-Based Biologics Approaches Used To Combat Autoimmune Disease Using Tnf-Α & Il Inhibitors.

Autoimmune disease is increasing widely, and the biologicals in autoimmune disease play a vital role in the cure. Biologicals have an affinity to bind the specific target molecule and suppress inflammation. The different biologicals are used to treat various autoimmune diseases by preventing the cytokines from unlocking cells and causing inflammation. Each biologic targets a different cytokine. The common classes of biologic that are used to treat autoimmune disease are i) Tumor Necrosis Factor-alpha (TNFα) inhibitors and ii) Interleukin Inhibitors (IL). Along with biologics, nanomedicine has shown to be a successful method for creating customized nanomaterials with the potential to deliver medicinal agents to particular organs or tissues drugs without causing immunosuppressive or immunostimulatory adverse effects. This article reviews biologics used in treating Autoimmune Disease (AD) and the mechanism involved. The examination of current developments that have been made to create innovative nanoparticle-based therapies for autoimmune illnesses and their inclusion in vaccines. Also, recent clinical trials display nanosystem strategies for treating AD.

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.

P-503 Immunological therapies in women undergoing assisted conception: a systematic review and meta-analysis

Abstract Study question What is the effectiveness and safety of immunological therapies in women undergoing assisted conception? Summary answer The evidence on the overall effectiveness and safety of immunomodulators was scarce and uncertain, although some drugs may lead to improved outcomes in selected women. What is known already Embryo implantation is a pre-requisite for pregnancy success. It requires a state of immune tolerance within the maternal endometrium permitting the attachment and subsequent invasion into the decidua of the semi-allogenic blastocyst. Mechanistic data suggesting that heightened immune responses may impair implantation have led to the widespread use of immunomodulatory therapies in clinical practice. These include drugs such as aspirin, heparin, corticosteroids, intralipid and intravenous immunoglobulin (IVIG). However, despite the common use of immunomodulatory drugs in women having in vitro fertilisation (IVF), there is no consensus on their effectiveness and safety, owing to a paucity of well-designed interventional studies. Study design, size, duration We searched MEDLINE, EMBASE, PubMed and CENTRAL until September 2022. We selected randomised controlled trials (RCTs) investigating immunological therapies in women undergoing IVF, including aspirin, heparin, corticosteroids, granulocyte-colony stimulating factor (G-CSF), intralipid, intravenous immunoglobulin (IVIG), tumour necrosis factor-alpha inhibitors and peripheral blood mononuclear cells (PBMCs), evaluated alone or in combination, versus no intervention, placebo or any other immunomodulator(s). The primary outcomes were the rates of live birth or ongoing pregnancy (LBR/OPR) and miscarriage per participant. Participants/materials, setting, methods Two reviewers independently selected studies and extracted data. We conducted pairwise meta-analyses according to participants’ phenotypes as reported by the trialists, including: good prognosis, previous implantation failure, autoimmunity, high inflammation, thin endometrium, and low ovarian reserve. Using the Cochrane-RoB-1 tool, we restricted our primary analyses to RCTs at low risk of selection and other biases. We presented effect estimates as risk ratio (RR) with 95% confidence interval (CI) and considered I2&amp;gt;50% as representing substantial heterogeneity. Main results and the role of chance Our searches identified 14,893 records. We included a total of 84 studies in the qualitative synthesis, of which 43 contributed to the meta-analyses, evaluating in total 7,301 participants and 12 treatment comparisons. The primary analysis showed that aspirin resulted in little to no difference in LBR (RR 0.97, 95% CI 0.94-1.23; n = 688 women; moderate-certainty evidence) and MR (RR 1.20, 95% CI 0.73-1.99; n = 988 women; low-certainty evidence) compared with placebo. The data did not identify a difference in LBR/OPR in women using subcutaneous heparin (RR 1.30, 95% CI 0.80-2.12; n = 150 women; very low-certainty evidence) or IVIG (RR 1.28, 95% CI 0.32-5.16; n = 51 women; very low-certainty evidence) versus placebo. For the remaining interventions, the primary analysis was uncertain of an effect or insufficient for quantitative synthesis. However, the sensitivity analysis including all studies, irrespective of risk of bias, showed that corticosteroids may improve LBR in women with thyroid autoimmunity (RR 2.33, 95% CI 1.04-5.25; n = 60 women; very low-certainty evidence); intrauterine G-CSF may improve LBR in women with a thin endometrium (RR 2.57, 95% CI 1.24-5.29; n = 304 women; very low-certainty evidence); and intrauterine PBMCs may improve LBR in women with previous implantation failure (RR 2.03, 95% CI 1.33-3.10; n = 312 women; very low-certainty evidence). Limitations, reasons for caution For most of the interventions under study, the evidence was of low or very-low certainty, owing to limitations in study design, imprecision, indirectness and inconsistency. Further, very few studies reported on adverse events, highlighting a worrying lack of data on the safety of immunological therapies for women undergoing assisted conception. Wider implications of the findings A scarcity of well-designed RCTs limits the evidence on immunomodulators in women undergoing IVF. However, we identified positive signals for some therapies in specific conditions (e.g. corticosteroids for thyroid autoimmunity, intrauterine G-CSF for thin endometrium, and PBMCs in women with previous implantation failure). This merits further investigation in high-quality trials. Trial registration number PROSPERO registration number CRD42021294031

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.

Miliary Tuberculosis in a Patient With Ulcerative Colitis Treated With Tofacitinib

ABSTRACT Immunosuppression with tumor necrosis factor-alpha inhibitors and tofacitinib is a risk factor for reactivation of latent tuberculosis (TB) and the development of active TB. We report a case of miliary TB in a patient on treatment with tofacitinib for active ulcerative colitis. By week 4 of therapy, a clinical response was achieved. Subsequently, although being on treatment, the patient started having fever with night sweats and myalgias. The investigative workup revealed pulmonary miliary TB. Tofacitinib was withdrawn, and antitubercular therapy was initiated. The patient responded, both clinically and radiologically, to the antitubercular therapy. This case report highlights the importance of screening for latent TB in patients receiving tofacitinib.

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]

Pustular psoriasis: A distinct aetiopathogenic and clinical entity.

Pustular psoriasis is a distinct subset of psoriasis that presents with involvement of the skin in the form of sterile pustules along with systemic manifestations. Though it has been conventionally grouped under the umbrella of psoriasis, recent research has shed light on its pathogenetic mechanisms associated with the IL-36 pathway, which is distinct from conventional psoriasis. Pustular psoriasis in itself is a heterogeneous entity consisting of various subtypes, including generalised, localised, acute, and chronic forms. There is confusion regarding its current classification as entities like deficiency of IL-36 antagonist (DITRA) which are closely related to pustular psoriasis both in their pathogenetic mechanism and its clinical manifestations, are not included under pustular psoriasis. Entities like palmoplantar pustulosis, which presents with similar clinical features but is pathogenetically distinct from other forms of pustular psoriasis, are included under this condition. Management of pustular psoriasis depends upon its severity; while some of the localised variants can be managed with topical therapy alone, the generalised variants like Von Zumbusch disease and impetigo herpetiformis may need intensive care unit admission and tailor-made treatment protocols. The advent of newer biologics and better insight into the pathogenesis of pustular psoriasis has opened the way for newer therapies, including tumour necrosis factor-alpha inhibitors, interleukin-1 inhibitors, interleukin-17 inhibitors, and granulocyte monocyte apheresis. It continues to be an enigma whether pustular psoriasis is actually a variant of psoriasis or an entirely different disease entity, though we feel that it is an entirely different disease process.

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.

New Insight into the Molecular Pathomechanism and Immunomodulatory Treatments of Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is an immune-mediated inflammatory disorder characterized by deep-seated nodules, abscesses, sinus tracts and scars localized in the intertriginous areas. It is accompanied by pain, malodourous secretion and a dramatically decreased quality of life. Although the pathogenesis has not been entirely elucidated, the primary event is follicular hyperkeratosis of the pilosebaceous apocrine unit. Since the registration of the tumor necrosis factor-alpha inhibitor Adalimumab in 2015, several cytokines have been implicated in the pathomechanism of HS and the research of novel therapeutic targets has been intensified. We provide an update on the inflammatory cytokines with a central role in HS pathogenesis and the most promising target molecules of future HS management.

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.

Rise of biologics in noninfectious uveitis: a retrospective cohort study from Nepal.

A retrospective review of all cases of noninfectious uveitis and scleritis presenting to our center from July 2019 to January 2021 and had been treated with biological therapy were included. We included 12 eyes of 10 patients. The mean age was 42.10±9.71 years. Anterior nongranulomatous uveitis comprised 70% of the cases and the most common etiology of anterior uveitis was spondyloarthritis (seven cases among which five cases were nonradiographic) axial spondyloarthritis (human leukocyte antigen B27 positive) followed by radiographic axial spondyloarthritis (two cases). The first line of treatment in all cases was conventional synthetic disease-modifying antirheumatic agents among which 50% (n=5) had received methotrexate (≥15mg/week). As a second line of treatment, one or more biologics was used. Majority of the patients received oral tofacitinib 50% (n=5) followed by Inj adalimumab 30% (n=3). One case of Behcet's disease required sequential biologics (Inj adalimumab followed by oral tofacitinib). All patients tolerated and responded well to the treatment and no recurrences were observed after discontinuation of biologics drugs during the follow-up period of 1 year. Biologics are a relatively safe and effective modality of treatment in refractory, recurrent noninfectious uveitis.

Real-world effectiveness of golimumab in the treatment of patients with active rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis who failed initial TNF-α inhibitor therapy: a pooled analysis of European prospective observational studie.

Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) patients often experience secondary non-response to a first-line tumour necrosis factor alpha inhibitor (TNFαi). This pooled analysis of six observational studies in Europe (GO-BEYOND program) provides an estimate of second-line golimumab (GLM) effectiveness for these rheumatic diseases. The GO-BEYOND studies included common disease-specific endpoints allowing for a pooled analysis. Patients had discontinued one prior TNFαi (due to loss of efficacy, tolerability, or inconvenience) and were followed for 12 months after GLM initiation. Primary endpoints included the proportion of patients achieving low disease activity (LDA, DAS28-CRP<3.2) in RA, minimal disease activity (MDA, fulfilment of 5 of 7 outcome measures) in PsA, or low disease activity (ASDAS<2.1) in axSpA at 6 months. Disease activity at 3 and 12 months and quality of life (QoL; EQ-5D-3L) were also assessed. Adverse events were monitored. Protocol-specified analyses were based on observed data. In 712 patients, (n=325, RA; 186, PsA; 201, axSpA), mean age was 54 years, 64% were female, and median disease duration was 5 years. Primary endpoints were achieved in 58.3% (RA), 45.5% (PsA), and 45.4% (axSpA) of patients; disease activity improvements were observed at 3 and 12 months and EQ-5D-3L results showed improved QoL over time. The treatment persistence rate at 12 months was 67.8% of patients. No new safety signals were observed. This pooled analysis of the GO-BEYOND studies showed that treatment with GLM was effective and represented a valid second-line option for RA, PsA, and axSpA patients.

Biodegradable Microspheres and Hydrogel Drug Delivery System of Tumor Necrosis Factor (TNF) Inhibitor and Growth Differentiation Factor 5 (GDF5) Reduces Disk Inflammation in the Rabbit Model.

Preclinical study. Develop and test a drug delivery system (DDS) composed of anti-inflammatories and growth factors in the rabbit disk injury model. Biological therapies that inhibit inflammation or enhance cell proliferation can alter intervertebral disk (IVD) homeostasis to favor regeneration. As biological molecules have short half-lives and one molecule may not cover multiple disease pathways, effective treatments may require a combination of growth factors and anti-inflammatory agents delivered in a sustained manner. Biodegradable microspheres were generated separately to encapsulate tumor necrosis factor alpha (TNFα) inhibitors [etanercept (ETN)] or growth differentiation factor 5 (GDF5) and were embedded into a thermoresponsive hydrogel. Release kinetics and activity of ETN and GDF5 were measured in vitro . For in vivo testing, New Zealand White rabbits (n=12) underwent surgery for disk puncture and treatment with blank-DDS, ETN-DDS, or ETN+GDF5-DDS at levels L34, L45, and L56. Radiographic and magnetic resonance images of the spines were obtained. The IVDs were isolated for histologic and gene expression analyses. ETN and GDF5 were encapsulated into poly (L-lactide-co-glycolide) microspheres and had average initial bursts of 2.4±0.1 and 11.2±0.7μg from DDS, respectively. In vitro studies confirmed that ETN-DDS inhibited TNFα-induced cytokine release and GDF5-DDS induced protein phosphorylation. In vivo studies showed that rabbit IVDs treated with ETN+GDF5-DDS had better histologic outcomes, higher levels of extracellular, and lower levels of inflammatory gene expression than IVDs treated with blank-DDS or ETN-DDS. This pilot study demonstrated that DDS can be fabricated to deliver sustained and therapeutic dosages of ETN and GDF5. In addition, ETN+GDF5-DDS may have greater anti-inflammatory and regenerative effects than ETN-DDS alone. Thus, intradiscal injection of controlled release TNF-α inhibitors and growth factors may be a promising treatment to reduce disk inflammation and back pain.

Efficacy and pharmacokinetics of ozoralizumab, an anti-TNFα NANOBODY® compound, in patients with rheumatoid arthritis: 52-week results from the OHZORA and NATSUZORA trials

IntroductionOzoralizumab (OZR), a tumor necrosis factor alpha (TNFα) inhibitor, is a NANOBODY® compound that binds to TNFα and human serum albumin. The main objective of this study was to analyze the pharmacokinetics (PK) of the drug and its correlation with clinical efficacy in patients with rheumatoid arthritis (RA).MethodsEfficacy data were analyzed from the OHZORA trial, in which OZR 30 or 80 mg was administered to Japanese patients with RA at 4-week intervals for 52 weeks in combination with methotrexate (MTX; n = 381), and the NATSUZORA trial, in which OZR 30 or 80 mg was administered without concomitant MTX (n = 140). Effects of patient baseline characteristics and anti-drug antibodies (ADAs) on the PK and efficacy of OZR were investigated, and a post hoc analysis of PK effects on drug efficacy was performed.ResultsThe maximum plasma concentration (Cmax) was reached in 6 days in both the 30 and 80 mg groups, with an elimination half-life of 18 days. The Cmax and area under the plasma concentration–time curve increased in a dose-dependent manner, and the trough concentration reached steady state by week 16. The exposure of OZR correlated negatively with patient body weight and was not affected by other patient baseline characteristics. Effects of ADAs on the exposure and efficacy of OZR were limited in both trials. However, antibodies that neutralize the binding to TNFα had some effect on the exposure and efficacy of OZR in the NATSUZORA trial. The receiver operating characteristic analysis of the effect of trough concentration on the American College of Rheumatology 20% and 50% improvement rates was retrospectively performed, and a cutoff trough concentration of approximately 1 μg/mL at week 16 was obtained in both trials. The efficacy indicators in the subgroup with trough concentration ≥ 1 μg/mL were higher than those in the < 1 μg/mL subgroup at week 16, while no clear cutoff was obtained at week 52 in both trials.ConclusionsOZR showed a long half-life and favorable PK properties. A post hoc analysis suggested sustained efficacy independent of trough concentration by subcutaneous administration of OZR 30 mg at 4-week intervals for 52 weeks.Trial registrationJapicCTI, OHZORA trial: JapicCTI-184029, registration date July 9, 2018; NATSUZORA trial: JapicCTI-184031, registration date July 9, 2018.