Efficacy and safety of risankizumab for Crohn's disease in patients from Asian countries: a post hoc subanalysis of the global phase 3 ADVANCE, MOTIVATE, and FORTIFY studies.

BACKGROUND AND AIM: The anti-interleukin-23 antibody risankizumab is being investigated as a treatment for moderate-to-severe Crohn's disease. This post hoc subanalysis evaluates the efficacy and safety of risankizumab therapy in Asian patients. METHODS: ADVANCE (NCT03105128) and MOTIVATE (NCT03104413) were randomized, double-blind, placebo-controlled, phase 3 induction studies. Patients with intolerance/inadequate response to biologic (MOTIVATE) and/or conventional therapy (ADVANCE) were randomized to receive intravenous risankizumab (600 or 1200 mg) or placebo at weeks 0, 4, and 8. Clinical responders to risankizumab could enter the phase 3, randomized, double-blind, placebo-controlled maintenance withdrawal study (FORTIFY; NCT03105102). Patients were rerandomized to receive subcutaneous risankizumab (180 or 360 mg) or placebo (withdrawal) every 8 weeks for 52 weeks. RESULTS: Among 198 Asian patients in the induction studies, clinical remission and endoscopic response at week 12 were achieved by 61.4% and 40.0%, 59.5% and 35.8%, and 27.3% and 9.1% of patients in the risankizumab 600 mg, risankizumab 1200 mg, and placebo groups, respectively. Among 67 patients who entered the maintenance study, clinical remission and endoscopic response at week 52 were achieved by 57.1% and 52.4%, 75.0% and 40.0%, and 53.8% and 34.6% of patients in the risankizumab 180 mg, risankizumab 360 mg, and placebo (withdrawal) groups, respectively. Fistula closure was observed with risankizumab treatment in 28.6% (induction) and 57.1% (maintenance) of patients. Efficacy trends and safety profile were similar to those in non-Asian patients. CONCLUSION: Consistent with non-Asian and global population results, risankizumab was effective and well tolerated in Asian patients with Crohn's disease.

Risankizumab to treat moderately to severely active Crohn's disease in adults: an evaluation of trials and data.

INTRODUCTION: Risankizumab is a humanized monoclonal antibody that selectively inhibits interleukin (IL)-23. It is approved for the treatment of moderate-to-severe plaque psoriasis, psoriatic arthritis, and more recently moderate-to-severe Crohn's disease (CD). AREAS COVERED: After examining the current landscape of CD management including therapies which are currently approved and those in late stages of development, we will review the interleukin pathway and discuss the specific mechanism of targeted IL-23 inhibition, summarize available clinical trial data on efficacy and safety of Risankizumab, consider future positioning of Risankizumab in the therapeutic armamentarium, and ultimately discuss future needs for the field. EXPERT OPINION: Risankizumab represents the first and only targeted IL-23 inhibitor approved for the treatment of CD, providing a promising addition to the therapeutic armamentarium for CD, with a favorable safety profile and demonstrated efficacy in both biologic-naïve and exposed populations. It is possible that the targeted nature of Risankizumab may enhance efficacy and safety over combined IL-12/23 inhibition, with trials underway attempting to shed light on that hypothesis.

Risankizumab in Adults with Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease associated with psoriasis. Its major clinical domains include peripheral and axial arthritis, enthesitis, dactylitis and skin and nail involvement. Approximately 30% of patients with psoriasis develop psoriatic arthritis. The pathophysiology of PsA is complex and involves a dysregulated immune response. In particular, interleukin (IL)-23 is a major regulatory cytokine that has been implicated in PsA, including bone remodeling, enthesitis, synovitis and psoriatic lesions. Risankizumab is a humanized immunoglobulin G1 monoclonal antibody that targets the p19 subunit of IL-23. It has been approved for the treatment of moderate-to-severe plaque psoriasis and, more recently, PsA. The efficacy and safety of risankizumab for the treatment of PsA has been demonstrated in phase 2 and phase 3 clinical trials. Risankizumab showed efficacy in decreasing the number of swollen and tender joints, clearing psoriatic plaque and improving quality of life. Treatment with risankizumab was well-tolerated, with the most common adverse event being upper respiratory tract infection. Overall, the current literature demonstrates that risankizumab is both a safe and effective therapeutic option for the treatment of PsA. Herein, week 24 and 52 results are reviewed.

Psoriasis: Striving for Potential Biomarkers.

Psoriasis is a chronic disease that is caused by multiple factors and is identified by itchiness, unpleasant, red, or white scaly patches on the skin, particularly on regularly chafed body regions such as the lateral areas of the limbs. Reports suggest that globally around 2%-3% of the population suffers from psoriasis. In this review, we have discussed the clinical classification of psoriasis and also the ideal characteristics of the biomarkers. An overview regarding the discovery of the biomarker and method for validating the study has been discussed. A growing body of research suggests a link to certain other systemic symptoms such as cardiovascular disorder, metabolic syndrome, and few other comorbidities such as hypertension and nonalcoholic fatty liver disease. Natural killer (NK) cells are lymphocyte cells that concentrate on the destruction of virally infected and malignant cells; these tend to produce a wide range of inflammatory cytokines, some of which are associated with the etiology of psoriasis. Detailed information on the molecular pathogenesis of psoriasis in which interleukin (IL)-17, IL-23, tumor necrosis factor-α (TNF-α), and CCL20 play a very significant role in the development of psoriasis. In this review, we have discussed an overview of the recent state of the biomarkers available for the diagnosis and treatment of psoriasis by emphasizing on the available biomarkers such as epigenomic, transcriptomic, glycomic, and metabolomic. The most recent advancements in molecular-targeted therapy utilizing biologics and oral systemic therapy (methotrexate, apremilast) enable to adequately treat the most serious psoriatic symptoms and also the studies have validated the efficacy of biologic therapy such as TNF-α antagonist (infliximab, adalimumab), IL-23 antagonist (guselkumab, risankizumab), and IL-17 antagonist (secukinumab, ixekizumab). Finally, an overview about the technological opportunities as well as various challenges has been discussed.

Pulmonary fibrosis and type-17 immunity.

Fibrosis of the lung can occur in idiopathic pulmonary fibrosis, collagen vascular diseases, and hypersensitivity pneumonitis, among other diseases. Transforming growth factor (TGF)-ß, vascular epithelial growth factor, fibroblast growth factor, and platelet-derived growth factor contribute to the pathophysiology of fibrosis. TGF-ß and other cytokines, including interleukin (IL)-1ß, IL-6, and IL-23, activate type-17 immunity, which is involved in pulmonary fibrosis. The components of type-17 immunity include type-17 helper T cells, γδT cells, IL-17A-producing CD8-positive T cells, invariant NKT cells, and group 3 innate lymphoid cells. IL-17A, the main cytokine of type-17 immunity, is able to induce the epithelial-mesenchymal transition in epithelial cells via a production of TGF-ß, directly stimulate fibroblasts and fibrocytes, and inhibit autophagy, which otherwise protects against pulmonary fibrosis. IL-23 induces type-17 immunity and plays an important role in the acute exacerbation of pulmonary fibrosis. Clinical studies have also linked type-17 immunity to the pathogenesis of pulmonary fibrosis. Consequently, targeting type-17 immunity may serve as a new therapeutic strategy to prevent the development or exacerbation of pulmonary fibrosis.

Safety of IL-23 p19 Inhibitors for the Treatment of Patients With Moderate-to-Severe Plaque Psoriasis: A Narrative Review.

The approved biologics targeting interleukin (IL)-23 p19 for the treatment of moderate-to-severe plaque psoriasis, including guselkumab, tildrakizumab, and risankizumab, have generally favorable safety profiles. The aim of the current review is to describe in detail the safety of these selective inhibitors. A literature search was performed using PubMed from inception to 1 November 2022, to identify clinical trials and real-world evidence publications using the keywords "guselkumab," "tildrakizumab," and "risankizumab." Overall, the most common adverse events (AEs) associated with IL-23 p19 inhibitors in clinical trials were nasopharyngitis, headache, and upper respiratory tract infections. Rates of serious AEs and AEs of interest, including serious infections, nonmelanoma skin cancer (NMSC), malignancies excluding NMSC, major adverse cardiovascular events, and serious hypersensitivity reactions, were not increased with long-term use in clinical trials. Selectively targeting IL-23 p19 was also not associated with elevated risk of opportunistic infections, tuberculosis reactivation, oral candidiasis, or inflammatory bowel disease. Results from real-world studies were similar, supporting the safe long-term use of these biologics in a wider population of patients with psoriasis, including older patients, patients for whom multiple biologics failed, and those with comorbidities such as obesity, metabolic syndrome, cardiovascular disease, dyslipidemia, diabetes, hypertension, and psoriatic arthritis. This review is limited by the lack of direct comparisons among therapeutic agents due to differences among study designs and safety data reporting methods. In conclusion, the favorable safety profiles of IL-23 p19 inhibitors support their long-term use in the management of patients with moderate-to-severe psoriasis.

Effect of body mass index on treatment response of biologic/targeted-synthetic DMARDs in patients with rheumatoid arthritis, psoriatic arthritis or axial spondyloarthritis. A systematic review.

BACKGROUND: Overweight and/or obese patients with inflammatory arthritis (IA) have higher disease activity and lower chances of achieving and/or maintaining the treatment targets. Weight/obesity also appears to negatively affect the response to tumor necrosis factor (TNF) inhibitors in IA patients, including rheumatoid arthritis -RA, psoriatic arthritis -PsA, axial spondyloarthritis -AxSpA. We conducted a systematic literature review (SLR) for the effect of weight/body-mass-index (BMI) in the efficacy of all approved biologic (b) and targeted-synthetic (ts) DMARDs for the treatment of IA. METHODS: For this PROSPERO-registered SLR, we searched PubMed, Scopus and Cohrane-Library from inception up to June 21st 2022. Clinical-trials (randomized and non-randomized) and observational studies of RA, PsA or AxSpA patients that reported the effect of weight/BMI on response (all possible outcomes) to b/ts-DMARDs were included. Risk-of-bias was assessed via RoB2-Cochrane-tool and Newcastle-Ottawa-scale for randomized and non-randomized studies, respectively. FINDINGS: Out of 996 references, 75 eventually fulfilled the inclusion criteria (of which 10 studies were retrieved through manual-search). Among the included studies (TNF-inhibitors: 34, IL-12/23 inhibitors: 4, IL-23 inhibitor: 1, IL-17 inhibitors: 7, tocilizumab: 18, abatacept: 8, rituximab: 3, JAK-inhibitors: 5), most had medium RoB. Efficacy of TNF-inhibitors was affected by BMI in all forms of IA. Data are not robust to compare the effect among various TNF-inhibitors. In contrast, favorable results of IL-23 and IL-17 inhibitors did not appear to be influenced by increased BMI in PsA or AxSpA patients. Similar evidence exists for tocilizumab (in RA) and for abatacept (in RA and PsA), while no conclusion can be drawn for rituximab. More data are needed for JAK-inhibitors, although the effect of weight/BMI does not seem to be significant so far. INTERPRETATION: Weight/BMI should be considered in the treatment-plan of IA patients, with its effect being more pronounced for TNF-inhibitors compared to other b/ts-DMARDs.

The Impact of Proinflammatory Cytokines and Imiquimod on GLUT1 in HaCaT Keratinocytes - a Potential Anti-Psoriatic Therapeutic Target?

BACKGROUND/AIMS: Glucose metabolism has been proven as an essential process for proliferating keratinocytes, which highlights the importance of glucose transporter-1 (GLUT1) not only in the onset of psoriasis but also in the progression and severity of this inflammation-driven disease. In this study, we attempted to find a connection between proinflammatory cytokines (IL-6, IL-17, IL-23, IL-36, TNF-α), a skin inflammation inducing agent - imiquimod (IMQ) and GLUT1 expression. METHODS: Human keratinocyte HaCaT cell line was incubated with exogenous cytokines: IL-6, IL-17A, IL-23, IL-36, TNF-α at a final concentration of 100 ng/ml, or with 1 µM of IMQ, for 48 h. Following the stimulation, glucose uptake and GLUT1 expression were evaluated. The activity of GLUT1 was measured in the presence of a selective GLUT1 inhibitor, BAY-876. The expression of GLUT1 was examined by immunofluorescence and quantified by qPCR, Western blotting and densitometry. RESULTS: The results from qPCR analysis showed that the administration of exogenous IL-6, IL-17, IL-23 and IL-36 to HaCaT cells resulted in upregulation of GLUT1-encoding SLC2A1 gene, while TNF-α had no significant effect. The same results were confirmed by immunofluorescence analysis, as the fluorescent intensity of GLUT1 was elevated following cytokine and IMQ stimulation. Western blot and densitometry showed that all examined cytokines, as well as IMQ, increased GLUT1 expression. HaCaT cells displayed an improved intracellular 2-deoxy-D-glucose (2-DG) uptake and GLUT1 activity after stimulation by exogenous cytokines and IMQ. The highest uptake of 2-DG was observed after IL-23 stimulation (1.93x) and the lowest after TNF-α stimulation (1.07x). BAY-876 inhibited the 2-DG uptake compared to control. CONCLUSION: Our findings suggest that cytokines and IMQ may play a key role in regulating GLUT1 expression in HaCaT cells. We believe that GLUT1 overexpression could potentially be utilized in the targeted treatment of psoriasis.

Efficacy of guselkumab, a selective IL-23 inhibitor, in Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA): protocol of a randomised, double-blind, placebo controlled multicentre trial.

INTRODUCTION: Psoriatic arthritis (PsA) is a complex, immune-mediated disease associated with skin psoriasis that, if left untreated, can lead to joint destruction. Up to 30% of patients with psoriasis progress to PsA. In most cases, psoriasis precedes synovio-entheseal inflammation by an average of 5-7 years, providing a unique opportunity for early and potentially preventive intervention in a susceptible and identifiable population. Guselkumab is an effective IL-23p19 inhibitor Food and Drug Administration (FDA-approved for treatment of moderate-to-severe psoriasis and PsA. The Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA) study aims to evaluate the efficacy of guselkumab in preventing PsA and decreasing musculoskeletal power Doppler ultrasound (PDUS) abnormalities in a population of patients with psoriasis who are at-increased risk for PsA progression. METHODS AND ANALYSIS: The PAMPA study is a multicentre, randomised, double-blind, placebo-controlled, interventional, preventive trial comparing PDUS involvement and conversion to PsA in patients with psoriasis at-increased risk for progression treated with guselkumab compared with non-biological standard of care. The study includes a screening period, a double-blind treatment period (24 weeks) and an open-label follow-up period (72 weeks). At baseline, 200 subjects will be randomised (1:1) to receive either guselkumab 100 mg (arm 1) or placebo switching to guselkumab 100 mg starting at week 24 (arm 2). Arm 3 will follow 150 at-risk psoriasis patients who decline biological therapy and randomisation. Changes from baseline in the PDUS score at week 24 and the difference in proportion of patients transitioning to PsA at 96 weeks will be examined as the coprimary endpoints. ETHICS AND DISSEMINATION: Ethics approval for this study was granted by the coordinating centre's (NYU School of Medicine) Institutional Review Board (IRB). Each participating site received approval through their own IRBs. The findings will be shared in peer-reviewed articles and scientific conference presentations. TRIAL REGISTRATION NUMBER: NCT05004727.

Current Knowledge on Psoriasis During the Covid-19 Pandemic.

Psoriasis is a chronic inflammatory disease associated with a defective epidermal barrier, in which the immune system is already activated in lesional sites of the skin, and it is thus possible that affected individuals can have different immunologic rates of viral response. This is especially important in the era of the novel coronavirus disease (COVID-19) that is affecting the entire world. Patients with psoriasis are often receiving systemic therapy which includes immunosuppressive and biologic therapy, so this new infectious disease has raised concerns among dermatologists regarding psoriasis treatment. Some of the risk factors of psoriasis are obesity, diabetes mellitus, and hypertension - all of which are diseases linked with negative outcomes and higher severity of COVID-19. Psoriasis is mediated by inflammatory cells and proinflammatory cytokines such as IL-17, IL-23, IFN-γ, and TNF-α, and patients with skin diseases have been shown to be more susceptible to COVID-19 infection, but with a less severe disease course. As an anti-inflammatory agent, vitamin D could play a significant role in the future as a possible treatment for reducing the risk and severity of psoriasis and COVID-19. It has been suggested that patients treated with biologic therapy should continue treatment, as it has not been shown to cause severe complications of the COVID-19 disease. Preventive measures, including vaccination, should be taken to minimize the risk of infection and severity of the clinical outcome.

Challenges in Noninvasive Skin Biomarker Measurements in Daily Practice: A Longitudinal Study on Skin Surface Protein Detection by the Transdermal Analysis Patch in Pediatric Psoriasis.

INTRODUCTION: Skin surface proteins are potential biomarkers in psoriasis and can be measured noninvasively with the transdermal analysis patch (TAP). This study aimed to assess markers measured by TAP over time in daily clinical practice, explore their correlation with disease severity in pediatric psoriasis, and compare the TAP and tape stripping detection capability. METHODS: In this prospective observational daily clinical practice study, pediatric psoriasis patients (aged >5 to <18 years) were followed during 1 year. At each visit, TAPs were applied to lesional (n = 2), peri-lesional (n = 2), and non-lesional (n = 1) sites. Post-lesional skin was sampled if all lesions on the arms, legs, or trunk cleared. Treatment and psoriasis severity data were collected. IL-1RA, hBD-2, IL-1α, IL-8, VEGF, CXCL-1/2, CCL-27, IL-23, hBD-1, IL-22, IL-17A, KLK-5, and IL-4 levels were quantified by spot-ELISA. For the statistical analysis, Wilcoxon signed rank tests, Mann-Whitney U tests, and Spearman correlations were used. Detection capability of the TAP was compared to tape stripping in a separate cohort of adult psoriasis patients. RESULTS: 32 patients (median age 15.0 years, median Psoriasis Area and Severity Index [PASI] 5.2) were followed for a mean of 11.3 (±3.4) months with a total of 104 visits. In lesional skin (n = 197), significantly higher IL-1RA, hBD-2, IL-8, VEGF, CXCL-1/2, IL-23, hBD-1, IL-22, CCL-27, and IL-17A levels were found compared to non-lesional skin (n = 104), while IL-1α was higher in non-lesional skin. Marker levels were highly variable over time and did not correlate with disease severity measured by PASI or SUM scores. Comparison of the TAP and tape strip detection capability in adult psoriasis patients (n = 10) showed that lesional hBD-2, IL1-α, IL-8, and VEGF and non-lesional IL-1RA, hBD-2, IL-8, and VEGF were more frequently detected in tape extracts than TAPs. CONCLUSION: Due to the lack of correlation with clinical disease severity and the current detection capability of the markers measured by TAP in psoriasis, its use in regular practice is still a bridge too far.

Tacrolimus nanocrystals microneedle patch for plaque psoriasis.

Plaque psoriasis is characterized by an abnormal thickening of the epidermis, which causes great difficulties for traditional topical drug delivery. Microneedles can pierce the thickened epidermis and deliver drugs to the skin for psoriasis treatment. Tacrolimus is a poorly water-soluble immunosuppressant used for the treatment of psoriasis. In this study, tacrolimus (TAC) nanocrystals (NCs) were produced using a bottom-up technique that dispersed TAC into a sodium hyaluronate-based microneedle patch (MNP), and its therapeutic efficacy was evaluated. The average particle size of the TAC NCs was 259.6 ± 2.3 nm. The mechanical strength of the microneedles was 0.41 ± 0.06 N/needle, which was sufficient to penetrate psoriatic skin. Microneedles were detached from the substrate 10 min after insertion into the psoriasis skin with an insertion depth of 258.8 ± 14.4 µm. The intradermal retention of the MNP (8.40 ± 0.33 µg/cm2) was six times that of the commercial ointment (1.40 ± 0.12 µg/cm2). In pharmacodynamic experiments, results indicated improvement in the phenotypic and histopathological features and reduction in the level of TNF-α, IL-17A, and IL-23 of psoriatic skin treated with TAC NCs MNP. Therefore, MNP loaded with TAC NCs may be a promising approach for psoriasis treatment.

Tuscany consensus for the treatment of moderate-severe psoriasis: update and focus on practical guidelines for place in therapy of anti-IL-17 and anti-IL-23 biologics.

Psoriasis is a common chronic skin disease characterized by a worldwide distribution and a natural tendency towards progression. According to the many clinical forms, the extension of the disease and the many comorbidities, almost the 20% of the patients require a systemic treatment. Biologics have greatly changed the ongoing of psoriasis and the quality of life of psoriasis patients. After the anti-TNF-alpha, which were the first biologics in use for psoriasis, the improvement in knowledge of the pathogenetic mechanisms underlying the disease has led to the development of a series of more specific therapies for psoriasis. This "second generation" of biologics includes the interleukin (IL)-12/23 inhibitor ustekinumab, IL-17 inhibitors (secukinumab and ixekizumab), the IL-17 receptor A (IL-17RA) antagonist brodalumab, and the IL-23 inhibitors guselkumab, risankizumab and tildrakizumab. This study represents an update of the Tuscany consensus focused on the use of new drugs, such as anti-IL-17 and anti-IL-23 in moderate-to-severe psoriasis and their correct place in therapy according to specific clinical requests and in full respect of the current financial restrictions.

An Emerging Role of Proanthocyanidins on Psoriasis: Evidence from a Psoriasis-Like Mouse Model.

Background: Psoriasis is an immune-mediated, chronic inflammatory disease, and genetic, immune, oxidative stress (OS), and environmental factors are all thought to contribute to its occurrence. Proanthocyanidins (PCs) are natural flavonoids consisting of catechins and epicatechins which have anti-inflammatory and anti-OS activities. PCs have been widely used to treat various diseases, but reports regarding psoriasis are rare. Objective: To investigate the therapeutic effect and potential mechanisms of action of PCs in a psoriasis-like mouse model. Methods: Thirty male BALB/c hairless mice were assigned to six groups (n = 5): normal, model, low-dose PCs, medium-dose PCs, high-dose PCs, and control groups. The final five groups were dorsally exposed to 5% imiquimod (IMQ) cream once a day for 6 consecutive days, while the normal group received no intervention. Following the first day of IMQ application, mice in the PC-treated group were dosed with different amounts of PCs daily by oral gavage for six days, whereas mice in the control group received normal saline in the same way. One week later, skin lesions were evaluated by the severity of scoring system based on psoriasis area and severity index (PASI), and pathological alterations were assessed by hematoxylin-eosin (HE) staining. Indicators of inflammation or OS, such as interleukin- (IL-) 17, IL-23, phosphorylated-phosphatidylinositol 3-kinase (p-PI3K), phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), catalase (CAT), vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), and heme oxygenase-1 (HO-1), were determined by ELISA, RT-PCR, western blot, and immunohistochemistry (IHC) analysis. Results: IMQ administration induced the formation of large dark red plaques with thickly layered scales on the dorsal skin of mice; nevertheless, the lesions were substantially alleviated by PC administration. Histopathological alterations were observed in both model and control groups with epidermal hyperkeratosis, granulosa layer thinning, acanthosis, downward extension of rete ridges, dermal papillae expansion, capillary hyperplasia, and infiltration by inflammatory cells around blood vessels. These pathological changes, however, were restored by a range of doses of PCs, high-dose PCs in particular. Different doses of PCs significantly lowered the spleen index, levels of inflammatory or oxidative proteins (IL-17, IL-23, MDA, ROS, p-PI3K, and p-STAT3), and the mRNA expression of Il-17, Il-23, Vegf, and iNos. Protein and mRNA levels of anti-OS and anti-inflammatory biomarkers, including SOD, CAT, GSH, and HO-1, greatly increased after PC treatment, especially at the highest dose. Conclusions: Our findings reveal that PCs ameliorate psoriasis-like symptoms, suppressing the inflammatory response and mitigating OS damage in an IMQ-induced psoriasis-like mouse model. These effects are probably related to the inactivation of STAT3 and PI3K and activation of HO-1 signaling.

The inhibitory effect of tocilizumab on systemic bone loss and tendon inflammation in a juvenile Collagen-Induced arthritis rat model.

PURPOSE OF THE STUDY: Reduced Bone Mineral Density (BMD) is a prevalent comorbidity in Juvenile Idiopathic Arthritis (JIA). Enthesitis and other tendon abnormalities, such as tenosynovitis, tendinitis and tendon ruptures are, also, common extra-articular manifestations of the disease. The aim of the present study was to investigate the effect of tocilizumab, an antibody that binds the Interleukin-6 (IL-6) Receptor, on inflammation-related bone loss and tendon inflammation in an animal model of JIA. MATERIALS AND METHODS: The Collagen-Induced Arthritis (CIA) model was induced in male rats followed by intraperitoneal administration of tocilizumab for 8 weeks. Methotrexate, the most widely used Disease-Modifying Antirheumatic Drug in the management of JIA, was, also, administered, either as a monotherapy or as an add-on therapy to tocilizumab. BMD was evaluated with Micro-Computed Tomography (Micro-CT) and histopathological examination. Tendon damage was, also, assessed histologically. Finally, two pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNF-a) and Interleukin-23 (IL-23) were quantified in tendon tissues by ELISA analysis. RESULTS: Tocilizumab-treated animals exhibited a significantly improved trabecular microarchitecture on micro-CT analysis and histological examination. Tendon morphology was also improved. Anti-IL-6 treatment led to a significant decrease in TNF-a and IL-23 expression in tendon tissue. CONCLUSIONS: The results of the present study provide evidence that tocilizumab reduces inflammation-related bone loss and suppresses tendon inflammation in a juvenile CIA rat model. These findings offer perspectives for the management of osteoporosis and enthesitis in JIA.

Dose reduction of the new generation biologics (IL-17 and IL-23 inhibitors) in psoriasis: study protocol for an international, pragmatic, multicenter, randomized, controlled, non-inferiority study-the BeNeBio study.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease for which biologics are effective treatments. Dose reduction (DR) of the first generation biologics seems a promising way for more efficient use of expensive biologics. A substantial part of patients on tumor necrosis factor (TNF)-alfa inhibitors and ustekinumab could successfully lower their dose, after following a tightly controlled DR strategy. The objective of this study is to assess whether controlled DR of interleukin (IL)-17 and IL-23 inhibitors in psoriasis patients with low disease activity is non-inferior (NI) to usual care (UC). METHODS: This is an international, prospective, multicenter, pragmatic, randomized, non-inferiority trial. A total of 244 patients with stable low disease activity (Psoriasis Area and Severity Index (PASI) ≤ 5) for at least 6 months and using secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, or tildrakizumab in the standard dose, together with stable low disease activity, defined as a PASI ≤ 5 and Dermatology Life Quality Index (DLQI) ≤ 5 at the moment of inclusion, will be randomized 2:1 to DR or UC. In the DR group, dosing intervals will be prolonged stepwise to achieve 66% and 50% of the original dose. Disease activity is monitored every 3 months by PASI and DLQI. In case of disease flare (i.e., PASI and/or DLQI increase), treatment is adjusted to the previous effective dose. The primary outcome is the incidence proportion of persistent flares (PASI > 5 for ≥ 3 months), which will be compared between arms. Secondary outcomes include proportion of patients with successful DR, (course of) PASI and DLQI, serious adverse events (SAEs), health-related quality of life, costs, and pharmacokinetic profile. Outcomes of DR will be compared to UC. DISCUSSION: With this study, we aim to assess whether DR of IL-17 and IL-23 inhibiting biologics can be achieved for psoriasis patients with low disease activity, without losing disease control. Reducing the dose may lead to more efficient use of biologics. TRIAL REGISTRATION: ClinicalTrials.gov NCT04340076 . Registered on April 9 2020.

Bioengineering heterodimeric cytokines: turning promiscuous proteins into therapeutic agents.

The interleukin 12 (IL-12) family comprises a group of heterodimeric cytokines that can cope with a great variety of immune conditions as the microenvironment demands. By sharing cytokine and receptor subunits, IL-12 (comprised of p40/p35 subunits), IL-23 (p40/p19), IL-27 (p28/EBI3), and IL-35 (p35/EBI3) represent, as a whole, a highly versatile system participating in controlling the continuum from inflammation to tolerance. Promiscuity, a peculiar feature of those cytokines, is a powerful and economic means of producing individual factors with distinct activities via different combinations of a single set of subunits. Whereas IL-12 and IL-23 have a clearly dominant immunostimulatory functional profile and IL-35 is a potent immunosuppressive agent, IL-27 can exert both adjuvant and regulatory effects, depending on the cytokine milieu. Promiscuity itself, however, may significantly hamper the therapeutic use of heterodimeric cytokines. The subunits of a recombinant cytokine, when administered in its native form, will rapidly dissociate in vivo and reassociate with alternative partners, thus generating different heterodimeric or even homodimeric molecules (i.e., p40/p40) with unwanted effects. As in other areas, bioengineering has provided a formidable tool to overcome the constraints associated with the potential use of IL-12 family cytokines. The generation of several gene constructs expressing IL-12, IL-23, IL-27, IL-35, or even the homodimer p40/p40, in their monomerized, single-chain form has allowed us to unveil the efficacy of those molecules in several experimental settings, including neoplasia, viral infection, chronic inflammation, allergy and autoimmunity. Although work is still needed to obtain an overall picture of therapeutic vs. adverse effects of individual molecules before any use in humans, the new frontiers of bioengineering are now driving the production of completely new combinations of cytokine subunits that may further extend the potential clinical use of such eclectic proteins.

A comparative study of primary and recurrent human glioblastoma multiforme using the small animal imaging and molecular expressive profiles.

PURPOSE: Glioblastoma multiforme (GBM) is the most malignant brain tumor with the characteristics of highly infiltrative growth and recurrent rate. In this study, we used animal imaging and molecular expressive profiles to investigate the characteristics of the primary tumor (GBM-3) cells and recurrent tumor (S1R1) cells from different GBM patients. PROCEDURES: Bioluminescent imaging and 3T magnetic resonance imaging (MRI) were used for assessing the orthotopical tumor development of GBM cells harboring a polycistronic reporter gene system. Western blot analysis and quantitative polymerase chain reaction were used to compare the molecular expressive profiles of two types of GBM cells. RESULTS: S1R1 cells exhibited apparent invasive ability compared to GBM-3 cells using in vitro invasion assay. In vivo bioluminescent imaging showed that intracranial tumors are formed by both types of GBM cells, but the bioluminescent signal was also detected in the lumbar region at late-stage tumor formed by S1R1 cells. The MRI showed that intracranial tumors formed by S1R1 cells were highly infiltrative compared to that formed by GBM-3 cells. Additionally, these two GBM types expressed different patterns of molecules associated with tumor development. Moreover, the suppressive effects of interleukine-23 (IL-23) on xenograft tumors formed by both GBM types were detected using bioluminescent imaging. CONCLUSION: The current data suggest that the in vivo growth behaviors and therapeutic responses of the primary and recurrent human GBMs were comparable using the reporter gene imaging, and different molecular expressive profiles exist between these two GBM types.

Anti-leukemic properties of IL-12, IL-23 and IL-27: differences and similarities in the control of pediatric B acute lymphoblastic leukemia.

B acute lymphoblastic leukemia (ALL) is the most common pediatric hematologic malignancy. Although patient cure has reached an excellent rate, a minority of cases relapse and need novel therapies. IL-12, IL-23 and IL-27 belong to the IL-12 superfamily and exert immunological and anti-tumor functions. The latter can be mediated by activation of immune responses or by the direct activity on cancer cells. Recently, the role of IL-12, IL-23 and IL-27 in the control of pediatric B-ALL has been unveiled. Here, we discuss in a translational perspective the role of IL-12 family cytokines in pediatric B-ALL, highlighting similarities and differences in their mechanisms of action.