Therapies For Immune-mediated Inflammatory Diseases Research Articles

Estimating cancer risk in immune-mediated inflammatory diseases exposed to varying doses of tumour necrosis factor inhibitors.

The safety profile of high doses of tumour necrosis factor inhibitors (TNFi) therapy for cancer risk in immune-mediated inflammatory diseases (IMIDs) remains uncertain. We evaluated the risk of cancer development in patients with IMIDs exposed to standard and high doses of TNFi compared with those never exposed to TNFi. A cohort study was conducted using the Japanese claims database encompassing over 4.6 million individuals from 2013 to 2021. The study included patients aged 16years or older with new-onset IMIDs, such as inflammatory bowel disease, rheumatoid arthritis, or psoriasis, who had no cancer history. The subdistribution hazard ratios (SHR) for cancer risk in TNFi standard and high dose groups comparing with TNFi unexposed group were estimated using a Fine and Gray model that accounted for the competing risk of death unrelated to cancer. The high dose of TNFi was defined as either a dose escalation or shortening of the intervals during administrations from the standard dose treatment. We identified a total of 42,006 patients with new-onset IMIDs (40,573 in TNFi unexposed, 876 in TNFi standard dose, and 557 in TNFi high dose) and 1211 (2.8%) patients developed cancer, yielding an incidence rate of 787.8 (739.9-828.1) per 100,000 person-years. Neither the standard nor high doses of TNFi significantly increased the cancer risk (TNFi standard dose vs. TNFi unexposed, adjusted SHR, 0.65 [0.40-1.08]; TNF high dose vs. TNFi unexposed, adjusted SHR, 1.12 [0.67-1.87]). There is no association between varying doses of TNFi therapy and cancer risk in IMIDs.

Funding and conclusions of network meta-analyses on targeted therapies in inflammatory diseases: an overview

ObjectivesTo explore the association between industry funding and network meta-analyses’ (NMAs) conclusion, and the use in Clinical Practice Guidelines (CPGs) of NMAs. Study Design and SettingThis was an overview of NMAs and CPGs. We searched PubMed/MEDLINE, Epistemonikos, and several guideline databases up to February 18th 2023. We included CPGs from the last 5 years and NMAs of randomized controlled trials that evaluated targeted therapies in immune-mediated inflammatory diseases. Data extraction and outcome assessments were done in duplicate by independent authors. ResultsWe included 216 NMAs and 99 CPGs. 31% (67/216) were industry-funded. The proportion of industry-funded NMAs that cited one treatment as being best was 44% (25/57) compared to 26% (30/116) for nonindustry-funded (OR = 2.24 [1.15-4.39]; aOR = 1.76 [0.81-3.81]). The abstract's conclusion of 39/67 (58%) industry-funded and 69/149 (46%) nonindustry-funded NMAs were considered unsupported by the results (OR = 1.61 [0.90-2.89]; aOR = 1.40 [0.71-2.78]). All industry-funded NMAs that cited one treatment as best cited their own sponsored drug. 59/99 (60%) CPGs included at least one NMA, with 23/59 (39%) of them citing industry-funded NMAs. ConclusionsWe did not find evidence that industry-funded NMAs were more likely to have unsupported conclusions or to cite only one treatment as being best in their conclusions compared to non-industry-funded NMAs. However, almost all industry-funded NMAs favored their own treatments. Even though 40% of the CPGs did not rely on NMA, over a third of those who did used industry-funded NMAs. Limitations include the possible misclassification due to undisclosed funding and potential confounders that have not been accounted for.

COVID-19 Vaccination and Immunosuppressive Therapy in Immune-Mediated Inflammatory Diseases.

The COVID-19 vaccination program has probably been the most complex and extensive project in history until now, which has been a challenge for all the people involved in the planning and management of this program. Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy have required special attention, not only because of the particular haste in carrying out the process but also because of the uncertainty regarding their response to the vaccines. We now have strong scientific evidence that supports the hypothesis that immunosuppressive therapy inhibits the humoral response to vaccines against other infectious agents, such as influenza, pneumococcus and hepatitis B. This has led to the hypothesis that the same could happen with the COVID-19 vaccine. Several studies have therefore already been carried out in this area, suggesting that temporarily discontinuing the administration of methotrexate for 2 weeks post-vaccination could improve the vaccine response, and other studies with various immunosuppressive drugs are in the same line. However, the fact of withholding or interrupting immunosuppressive therapy when dealing with COVID-19 vaccination remains unclear. On this basis, our article tries to compile the information available on the effect of immunosuppressant agents on COVID-19 vaccine responses in patients with IMIDs and proposes an algorithm for the management of these patients.

Tyk2 Targeting in Immune-Mediated Inflammatory Diseases.

The Janus kinase (Jak)/signal transducer and activating protein (STAT) pathways mediate the intracellular signaling of cytokines in a wide spectrum of cellular processes. They participate in physiologic and inflammatory cascades and have become a major focus of research, yielding novel therapies for immune-mediated inflammatory diseases (IMID). Genetic linkage has related dysfunction of Tyrosine kinase 2 (Tyk2)-the first member of the Jak family that was described-to protection from psoriasis. Furthermore, Tyk2 dysfunction has been related to IMID prevention, without increasing the risk of serious infections; thus, Tyk2 inhibition has been established as a promising therapeutic target, with multiple Tyk2 inhibitors under development. Most of them are orthosteric inhibitors, impeding adenosine triphosphate (ATP) binding to the JH1 catalytic domain-which is highly conserved across tyrosine kinases-and are not completely selective. Deucravacitinib is an allosteric inhibitor that binds to the pseudokinase JH2 (regulatory) domain of Tyk2; this unique mechanism determines greater selectivity and a reduced risk of adverse events. In September 2022, deucravacitinib became the first Tyk2 inhibitor approved for the treatment of moderate-to-severe psoriasis. A bright future can be expected for Tyk2 inhibitors, with newer drugs and more indications to come.

Differential Contribution of NF-κB Signaling Pathways to CD4+ Memory T Cell Induced Activation of Endothelial Cells.

Endothelial cells (ECs) are important contributors to inflammation in immune-mediated inflammatory diseases (IMIDs). In this study, we examined whether CD4+ memory T (Tm) cells can drive EC inflammatory responses. Human Tm cells produced ligands that induced inflammatory responses in human umbilical vein EC as exemplified by increased expression of inflammatory mediators including chemokines and adhesion molecules. NF-κB, a key regulator of EC activation, was induced by Tm cell ligands. We dissected the relative contribution of canonical and non-canonical NF-κB signaling to Tm induced EC responses using pharmacological small molecule inhibitors of IKKβ (iIKKβ) or NF-κB inducing kinase (iNIK). RNA sequencing revealed substantial overlap in IKKβ and NIK regulated genes (n=549) that were involved in inflammatory and immune responses, including cytokines (IL-1β, IL-6, GM-CSF) and chemokines (CXCL5, CXCL1). NIK regulated genes were more restricted, as 332 genes were uniquely affected by iNIK versus 749 genes by iIKKβ, the latter including genes involved in metabolism, proliferation and leukocyte adhesion (VCAM-1, ICAM-1). The functional importance of NIK and IKKβ in EC activation was confirmed by transendothelial migration assays with neutrophils, demonstrating stronger inhibitory effects of iIKKβ compared to iNIK. Importantly, iIKKβ – and to some extent iNIK - potentiated the effects of currently employed therapies for IMIDs, like JAK inhibitors and anti-IL-17 antibodies, on EC inflammatory responses. These data demonstrate that inhibition of NF-κB signaling results in modulation of Tm cell-induced EC responses and highlight the potential of small molecule NF-κB inhibitors as a novel treatment strategy to target EC inflammatory responses in IMIDs.

P099 Invasive listeriosis in patients with immune-mediated inflammatory diseases on biologics and targeted therapies - a review of the literature

Abstract Background/Aims Listeria monocytogenes is a gram-positive bacterium found ubiquitously in the environment. Human infection is relatively rare and usually occurs after consumption of contaminated food. L. monocytogenes can cause an uncomplicated gastroenteritis in the immunocompetent. Vulnerable individuals are at risk of invasive disease. These include the elderly, pregnant women, neonates and people with impaired immunity, including those treated with biologics and targeted therapies for immune-mediated inflammatory diseases (IMIDs). Invasive listeriosis typically causes bacteraemia, meningoencephalitis and maternal-neonatal infection. Other reviews have described an association between TNF-alpha inhibitors and invasive listeriosis, however the impact of newer biologics and the JAK-inhibitors has not been described. Methods The literature was systemically reviewed to assess the incidence of invasive listeriosis in patients with IMIDs treated with biologics or targeted therapies using Ovid Medline, EMBASE and the Cochrane Database of Systematic Reviews. Papers including patients over 16 years of age with rheumatoid arthritis (RA), ankylosing spondylitis (AS), axial spondyloarthritis, psoriatic arthritis, psoriasis, inflammatory bowel disease (IBD), (ulcerative colitis or Crohn’s disease), managed with biologics or targeted therapies were included. Abstracts, case reports, case series, cohort studies, registry studies, randomised controlled trials and meta-analyses were included. Reports not published in English or not detailing the name of the biologic or targeted therapy used were excluded. The primary outcome was incidence of invasive listeriosis defined as isolation of L. monocytogenes from a normally sterile site. Results Thirty-eight case reports, three disease-specific registry analyses, two randomised controlled trials and one meta-analysis were included in the final results. Together these studies reported 75 cases of invasive listeriosis in patients with IMIDs on biologics and targeted therapies. Seventy cases were described in patients treated with TNF-alpha inhibitors (49 with infliximab, nine with adalimumab, one with certolizumab pegol, one with golimumab and ten with etanercept). Two cases were described in patients treated with IL-12/IL-23 inhibitors (one with ustekinumab and one with guselkumab), one case was described in a patient treated with a gut-selective integrin antagonist (vedolizumab), one case in a patient treated with tocilizumab (an IL-6 inhibitor) and one case in a patient treated with a JAK-inhibitor (tofacitinib). Thirty-four patients had RA, 31 had IBD, five had psoriatic arthritis, two had ankylosing spondylitis, one had both psoriasis and psoriatic arthritis, one had psoriasis and another an unknown IMID. The reporting of listeriosis cases with TNF-alpha inhibitors has remained fairly steady over time so this association is not purely an early reporting phenomenon. Conclusion Cases of invasive listeriosis have been reported across a range of different IMIDs, most often in patients with RA and IBD. Invasive listeriosis is not unique to patients treated with TNF-alpha inhibitors. The association between invasive listeriosis and other targeted therapies (e.g. IL-23 inhibition) needs further study. Disclosure V. Allen: None. E. Alveyn: None. J. Galloway: Honoraria; AbbVie, Celgene, Chugai, Gilead, Janssen, Eli Lilly, Pfizer, Roche and UCB.

Distinct fibroblast subsets drive inflammation and damage in arthritis.

SummaryThe identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune mediated inflammatory diseases (IMIDs)1,2. However it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue driven processes observed in IMIDs such as inflammation and damage3–5. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of FAPα+ fibroblasts suppressed both inflammation and bone erosions in murine models of resolving and persistent arthritis. Single cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα+ population: FAPα+ THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAPα+ THY1- destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPα+ THY1- fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα+ THY1+ fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell based therapies aimed at modulating inflammation and tissue damage.

Biological Therapies in Immune-Mediated Inflammatory Diseases: Can Biosimilars Reduce Access Inequities?

Biological therapies are an effective treatment for a range of immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis, psoriasis, and inflammatory bowel diseases. However, due to their high costs, considerable differences in their utilization exist across the world, even among the various European countries, with many countries restricting access despite professional society guideline recommendations. Adoption of biologics by healthcare providers has been particularly poor in many Central and Eastern European countries. Differences in utilization have also been observed across medical specialties, healthcare providers, and at a regional and national level. The objective of this paper is to provide an overview of the different market access policies for biologics in Europe and to investigate reasons for such differences. One of the potential solutions for providing broader access to IMID patients, where cost is the major barrier, is to encourage the use of biosimilars in place of their reference products. Biosimilars are generally less expensive alternatives to already licensed biological therapies and are approved on the basis that they are similar to the reference product in terms of quality, safety, and efficacy. Budget impact models predict considerable cost savings following the introduction of biosimilars in the next few years. These savings could be used to increase access to biologics and other innovative therapies.

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis?

The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.

Adherence to systemic therapies for immune-mediated inflammatory diseases in Lebanon: a physicians' survey from three medical specialties.

BackgroundImmune-mediated inflammatory diseases (IMIDs) are chronic conditions that may cause tissue damage and disability, reduced quality of life and increased mortality. Various treatments have been developed for IMIDs, including immune modulators and targeted biologic agents. However, adherence remains suboptimal.MethodsAn adherence survey was used to evaluate physicians’ beliefs about adherence to medication in IMID and to evaluate if and how they manage adherence. The survey was distributed to 100 randomly selected physicians from three different specialties. Results were analyzed by four academic experts commissioned to develop an action plan to address practical and perceptual barriers to adherence, integrating it into treatment goals to maximize outcomes in IMID, thereby elevating local standards of care.ResultsEighty-two physicians participated in this study and completed the questionnaire. Most defined adherence as compliance with prescribed treatment. Although the majority of surveyed physicians (74%) did not systematically measure adherence in their practice, 54% identified adherence as a treatment goal of equal or greater importance to therapeutic endpoints. Lack of time and specialized nursing support was reported as an important barrier to measuring adherence. The expert panel identified four key areas for action: 360° education (patient–nurse–physician), patient–physician communication, patient perception and concerns, and market access/cost. An action plan was developed centered on education and awareness, enhanced benefit–risk communication, development of adherence assessment tools and promotion of patient support programs.ConclusionNonadherence to medication is a commonly underestimated problem with important consequences. A customized target-based strategy to address the root causes of non-adherence is essential in the management of chronic immune-mediated diseases.

714 - Obesity is Associated with Inferior Response to Anti-TNF Therapy in Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis

714 - Obesity is Associated with Inferior Response to Anti-TNF Therapy in Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis

IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases

The cytokine interleukin-12 (IL-12) was thought to have a central role in T cell-mediated responses in inflammation for more than a decade after it was first identified. Discovery of the cytokine IL-23, which shares a common p40 subunit with IL-12, prompted efforts to clarify the relative contribution of these two cytokines in immune regulation. Ustekinumab, a therapeutic agent targeting both cytokines, was recently approved to treat psoriasis and psoriatic arthritis, and related agents are in clinical testing for a variety of inflammatory disorders. Here we discuss the therapeutic rationale for targeting these cytokines, the unintended consequences for host defense and tumor surveillance and potential ways in which these therapies can be applied to treat additional immune disorders.

Integration of Lyoplate Based Flow Cytometry and Computational Analysis for Standardized Immunological Biomarker Discovery

Discovery of novel immune biomarkers for monitoring of disease prognosis and response to therapy in immune-mediated inflammatory diseases is an important unmet clinical need. Here, we establish a novel framework for immunological biomarker discovery, comparing a conventional (liquid) flow cytometry platform (CFP) and a unique lyoplate-based flow cytometry platform (LFP) in combination with advanced computational data analysis. We demonstrate that LFP had higher sensitivity compared to CFP, with increased detection of cytokines (IFN-γ and IL-10) and activation markers (Foxp3 and CD25). Fluorescent intensity of cells stained with lyophilized antibodies was increased compared to cells stained with liquid antibodies. LFP, using a plate loader, allowed medium-throughput processing of samples with comparable intra- and inter-assay variability between platforms. Automated computational analysis identified novel immunophenotypes that were not detected with manual analysis. Our results establish a new flow cytometry platform for standardized and rapid immunological biomarker discovery with wide application to immune-mediated diseases.

The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis

BackgroundImmunogenicity of aTNFs is one of the mechanisms behind treatment failure.ObjectiveTo assess the effect of anti-drug antibodies (ADA) on drug response to infliximab, adalimumab and etanercept, and the effect of...