Treatment Of Immune-mediated Inflammatory Diseases Research Articles

Dual blockade of IL-17A and IL-36 pathways via a bispecific antibody exhibits enhanced anti-inflammatory potency

Antibody drugs targeting single inflammatory cytokines have revolutionized the treatment of immune-mediated inflammatory diseases. To investigate whether dual targeting interleukin-17 (IL-17) and IL-36 enhances anti-inflammatory activity, bispecific Ab HB0043 was generated by linking the single chain fragment variables (scFvs) from humanized anti-IL-36R antibody (HB0034) to the C-terminus of the heavy chain of anti-IL-17A IgG1 (HB0017) Fc using a flexible peptide linker. HB0043 largely maintained the binding affinities and biological activities of the two parent monoclonal antibodies (mAbs) in vitro. IL-17 and IL-36 cooperated to amplify the expression of pro-inflammatory and pro-fibrotic genes in normal human dermal fibroblasts (NHDF). However, HB0043 more effectively blocked IL-6 and IL-8 production in NHDF stimulated by IL-17A and IL-36 compared to two monoclonal antibodies. In a mouse model of Oxazolone (OXA)-induced atopic dermatitis and Imiquimod (IMQ)-induced skin inflammation, administration of both anti-IL17A mAb HB0017 and anti-mouse IL-36R surrogate antibody HB0034SA showed improved effectiveness in alleviating skin thickening and inflammation based on histological assessment. Further, in cynomolgus monkeys, HB0043 showed no enhanced target-related toxicity compared with the two parental mAbs in vivo and with a moderate increase in production of anti-drug antibodies. Together, dual blockade of IL-17A and IL-36R in the form of a bispecific antibody may have advantages in blocking the overlapping and non-overlapping functions of these two cytokines in skin inflammation that could not optimally be curtailed with single mAbs. In conclusion, as monotherapy may reach therapeutic celling for certain difficult-to-treat inflammatory and fibrotic diseases, dual targeting could potentially pave a way to combat these diseases.

Real-World Evidence of Clinical Outcomes of the Use of the Adalimumab Biosimilar SB5 in Rheumatic and Gastrointestinal Immune-Mediated Inflammatory Diseases: 12-Month Data from the PERFUSE Study.

There is a need for published data on real-world use of SB5, an adalimumab (ADL) biosimilar approved in Europe in 2017, on the basis of evidence from pre-clinical and analytic data as well as phase I and III clinical studies demonstrating equivalent efficacy and comparable pharmacokinetics, safety and immunogenicity profiles as the reference ADL. The purpose of this study was to estimate patient persistence on SB5 at 12 months post-initiation using clinical and healthcare claims data from the French Système National des Données de Santé (national healthcare claims database, SNDS) in addressing data gaps. PERFUSE is a 12-month, observational, multi-centre cohort study of patients with rheumatic or gastrointestinal immune-mediated inflammatory diseases (IMIDs) who initiated routine SB5 treatment between October 2018 and October 2020, either as their first ADL (naïve) or transitioning from another ADL (switched). Clinical data, including disease activity scores, C-reactive protein levels, and dosing information, were collected as available from patient records captured during routine visits to specialist physicians. Persistence data were supplemented with data from the French national healthcare claims database (SNDS). Analyses of clinical data were descriptive, while persistence was assessed using a Kaplan-Meier survival analysis. Overall, 911 patients were included: 507 from rheumatology centres [116 with rheumatoid arthritis (RA), 78 psoriatic arthritis (PsA), and 313 ankylosing spondylitis (AS)] and 404 from gastroenterology centres [316 with Crohn's disease (CD) and 88 ulcerative colitis (UC)]. Among naïve patients, 12-month remission/low activity rates were 58% for RA, 66% for PsA, 59% for AS, 94% for CD, and 85% for UC, increasing significantly from baseline for all indications (p < 0.05). Switched patients' remission rates remained stable between baseline and month 12 (M12) for all indications (p > 0.05). Persistence (95% CI) at M12 among naïve patients was 59% (46.5, 68.8) for RA, 65% (49.7, 77.1) for PsA, 56% (48.3, 62.6) for AS, 70% (63.0, 75.7) for CD, and 42% (30.7, 53.1) for UC, compared to 60% (42.7, 73.7) for RA, 57% (37.3, 72.1) for PsA, 55% (45.8, 64.0) for AS, 63% (53.4, 71.7) for CD, and 56% (27.2, 77.6) for UC among switched patients. No significant differences were observed between naïve and switched patients (p > 0.05). SNDS pairing provided information on 68 of the 132 patients (52%) who were lost to follow-up in the clinical database, of whom 57 (84%) were confirmed persistent at M12 and 11 (16%) non-persistent. Primary treatment failure (naïve patients) and patient decision (switched patients) were the most common reasons stated for treatment discontinuation. SB5 provides clinically effective treatment of both gastrointestinal and rheumatic IMIDs for naïve and switched patients, with no loss of control observed when switching. Persistence was comparable between naïve and switched populations, though the reasons for non-persistence differed. Trial registration number: Clinical Trials identifier NCT03662919. Trial registration date: 10 September 2018.

Targeting next-generation PDE4 inhibitors in search of potential management of rheumatoid arthritis and psoriasis

Immune-mediated inflammatory diseases (IMIDs) comprise a broad spectrum of conditions characterized by systemic inflammation affecting various organs and tissues, for which there is no known cure. The isoform-specific inhibition of phosphodiesterase-4B (PDE4B) over PDE4D constitutes an effective therapeutic strategy for the treatment of IMIDs that minimizes the adverse effects associated with non-selective PDE4 inhibitors. Thus, we report a new class of isoquinolone derivatives as next-generation PDE4 inhibitors for effective management of rheumatoid arthritis (RA) and psoriasis. Among the series, 8 compounds i.e. 1e, 1l, 1m, 1n, 1o, 2m, 2o and 3o showed promising PDE4B inhibition (>80 %) in vitro with IC50 ∼ 1.4–6.2 µM. The compound 1l was identified as an initial hit and was pursued for further studies. According to structure–activity relationship (SAR), an allyl group at C-4 position improved PDE4B inhibition. The correlation between in vitro activity data and binding affinities obtained via molecular docking suggested that the high-affinity binding to PDE4B is a prerequisite for the effective inhibition of PDE4B. Notably, the hit 1l showed selectivity towards PDE4B over PDE4D in vitro. Furthermore, 1l treatment (30 mg/kg) in the adjuvant-induced arthritis (AIA) rat model induced by complete Freund’s adjuvant (CFA) demonstrated anti-arthritic potential via ameliorating paw swelling and body weight, narrowing joint space, reducing excessive immune cells infiltration and pannus formation in addition to reducing mRNA expression of pro-inflammatory cytokines such as TNF-α and IL-6 in synovial tissues of experimental rats. Additionally, 1l reduced the hyper-proliferative state and colony forming potential of IMQ-induced psoriatic keratinocytes. The treatment of these cells with 1l markedly reduced the protein levels of Ki67 and mRNA levels of pro-inflammatory cytokines e.g. IL-17A and TNF-α suggesting its potent anti-psoriatic potential. Furthermore, 1l did not show any significant adverse effects when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at the tested concentrations (1–100 µM) and the NOAEL (no-observed-adverse-effect level) was found to be 100 µM. Thus, with promising anti-inflammatory effects both in vitro and in vivo along with PDE4B selectivity with an acceptable safety margin, 1l emerged as a new and promising inhibitor for further studies.

Revolutionizing Treatment for Immune-Mediated Inflammatory Diseases

We spoke to Dr Sara Marsal, MD PhD, coordinator of the DocTIS project, which aims to drastically improve the prognosis of immune-mediated inflammatory diseases (IMIDs) by identifying highly effective combinatorial therapies for these patients.

Comment on "Development and Validation of a META-Algorithm to Identify the Indications of Use of Biological Drugs Approved for the Treatment of Immune-Mediated Inflammatory Diseases from Claims Databases: Insights from the VALORE Project". [Response to Letter

Comment on "Development and Validation of a META-Algorithm to Identify the Indications of Use of Biological Drugs Approved for the Treatment of Immune-Mediated Inflammatory Diseases from Claims Databases: Insights from the VALORE Project". [Response to Letter

Development and Validation of a META-Algorithm to Identify the Indications of Use of Biological Drugs Approved for the Treatment of Immune-Mediated Inflammatory Diseases from Claims Databases: Insights from the VALORE Project

Development and Validation of a META-Algorithm to Identify the Indications of Use of Biological Drugs Approved for the Treatment of Immune-Mediated Inflammatory Diseases from Claims Databases: Insights from the VALORE Project

Safety, Pharmacokinetics, and Pharmacodynamics of Etrasimod: Single and Multiple Ascending Dose Studies in Healthy Adults.

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator in development for immune-mediated inflammatory diseases (IMIDs). Here, we report the human safety, pharmacokinetics, and pharmacodynamics of etrasimod obtained from both a single ascending dose (SAD; 0.1-5mg) study and a multiple ascending dose (MAD; 0.35-3mg once daily) study. Overall, 99 healthy volunteers (SAD n = 40, MAD n = 59) completed the 2 studies. Evaluated single and multiple doses were well tolerated up to 3mg without severe adverse events (AEs). Gastrointestinal disorders were the most common etrasimod-related AEs. Over the evaluated single- and multiple-dose ranges, dose-proportional and marginally greater-than-dose-proportional etrasimod plasma exposure were observed, respectively. At steady state, etrasimod oral clearance and half-life mean values ranged from 1.0 to 1.2 L/h and 29.7 to 36.4 hours, respectively. Dose-dependent total peripheral lymphocyte reductions occurred following etrasimod single and multiple dosing. Etrasimod multiple dosing resulted in reductions from baseline in total lymphocyte counts ranging from 41.1% to 68.8% after 21 days. Lymphocyte counts returned to normal range within 7 days following treatment discontinuation. Heart rate lowering from pretreatment baseline on etrasimod dosing was typically mild, with mean reductions seen after the first dose of up to 19.5bpm (5mg dose). The favorable safety, pharmacokinetic, and pharmacodynamic properties of etrasimod in humans supported its further development and warranted its investigation for treatment of IMIDs.

Comments on "Development and Validation of a META-Algorithm to Identify the Indications of Use of Biological Drugs Approved for the Treatment of Immune-Mediated Inflammatory Diseases from Claims Databases: Insights from the VALORE Project" [Letter

Comments on "Development and Validation of a META-Algorithm to Identify the Indications of Use of Biological Drugs Approved for the Treatment of Immune-Mediated Inflammatory Diseases from Claims Databases: Insights from the VALORE Project" [Letter

On the Interdisciplinary Treatment and Management of Patients with Immune-Mediated Inflammatory Diseases. A Study on Patients' Personal Experiences and Perspectives.

Immune-mediated inflammatory diseases (eg, axial spondylitis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and hidradenitis suppurativa) are common diseases that exert an extensive effect on the health-related quality of life, particularly when multiple concomitant conditions are present. Previous reports indicate that the traditional siloed approach to care can lead to a lack of patient centricity and inefficient disease management. In this article, we aimed to evaluate an interdisciplinary program for the treatment of immune-mediated inflammatory diseases compared to routine clinical practice. This was a mixed-method study, combining qualitative and quantitative data. Patients with co-occurrence of ≥2 immune-mediated inflammatory diseases treated in an interdisciplinary clinic (n = 48) or traditional usual care (n = 17) answered open-ended questions about their care experiences. Two independent coders blinded to patients' treatment group coded three aspects of the narratives provided by the patients' responses: Themes, Emotional valence, and Personal growth (ie, redemption). Themes were analyzed descriptively to explore possible differences between patients assigned to the interdisciplinary clinic and patients assigned to the usual care setting. Group differences in patients' emotional experiences were assessed, and we examined potential group differences in positive personal growth. Our findings indicate that an interdisciplinary combined clinic approach provides benefits for patients with multiple inflammatory diseases towards the usual setup. Patients experienced benefits on a number of specific quality-of-life themes including acceptance, optimism, disease understanding, personal growth, and better disease control. The narratives of the patients in the interdisciplinary group were significantly more emotionally positive and included more positive personal growth compared to the usual care group. The findings indicate a patient-reported benefit, especially from the holistic approach and cross-specialty combined consultations in an interdisciplinary clinic compared to usual specialized healthcare, which was underscored by narratives highlighting an overall improved quality of life.

Identification of a transcription factor network regulating anti-TNF mediated IL10 expression in human CD4+ T cells.

CD4+ T cells are key players in immune-mediated inflammatory diseases (IMIDs) through the production of inflammatory mediators including tumour necrosis factor (TNF). Anti-TNF therapy has revolutionized the treatment of several IMIDs and we previously demonstrated that in vitro treatment of human CD4+ T cells with anti-TNF promotes anti-inflammatory IL-10 expression in multiple subpopulations of CD4+ T cells. Here we investigated the transcriptional mechanisms underlying the IL-10 induction by TNF-blockade in CD4+ T cells, isolated from PBMCs of healthy volunteers, stimulated in vitro for 3 days with anti-CD3/CD28 mAb in the absence or presence of anti-TNF. After culture, CD45RA+ cells were depleted before performing gene expression profiling and chromatin accessibility analysis. Gene expression analysis of CD45RA-CD4+ T cells showed a distinct anti-TNF specific gene signature of 183 genes (q-value < 0.05). Pathway enrichment analysis of differentially expressed genes revealed multiple pathways related to cytokine signalling and regulation of cytokine production; in particular, IL10 was the most upregulated gene by anti-TNF, while the proinflammatory cytokines and chemokines IFNG, IL9, IL22, and CXCL10 were significantly downregulated (q-value < 0.05). Transcription factor motif analysis at the differentially open chromatin regions, after anti-TNF treatment, revealed 58 transcription factor motifs enriched at the IL10 locus. We identified seven transcription factor candidates for the anti-TNF mediated regulation of IL-10, which were either differentially expressed or whose locus was differentially accessible upon anti-TNF treatment. Correlation analysis between the expression of these transcription factors and IL10 suggests a role for MAF, PRDM1, and/or EOMES in regulating IL10 expression in CD4+ T cells upon anti-TNF treatment.

Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial

Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59-2·70; p<0·0001). No intervention-related serious adverse events occurred. 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. National Institute for Health and Care Research.

Type 1 interferons: A target for immune-mediated inflammatory diseases (IMIDs)

The improved understanding of the molecular basis of innate immunity have led to the identification of type I interferons (IFNs), particularly IFN-α, as central mediators in the pathogenesis of several Immune-mediated inflammatory diseases (IMIDs) such as systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis and Sjögren's syndrome. Here, we review the main data regarding the opportunity to target type I IFNs for the treatment of IMIDs. Type I IFNs and their downstream pathways can be targeted pharmacologically in several manners. One approach is to use monoclonal antibodies against IFNs or the IFN-receptors (IFNARs, such as with anifrolumab). The downstream signaling pathways of type I IFNs also contain several targets of interest in IMIDs, such as JAK1 and Tyk2. Of these, anifrolumab is licensed and JAK1/Tyk2 inhibitors are in phase III trials in SLE. Targeting IFN-Is for the treatment of SLE is already a reality and in the near future may prove useful in other IMIDs. IFN assays will find a role in routine clinical practice for the care of IMIDs as further validation work is completed and a greater range of targeted therapies becomes available.

Cardiovascular Risk Management in Patients Treated With Janus Kinase Inhibitors.

The Janus kinase-signal transducer and activator of transcription pathway plays a critical role in the pathogenesis of many immune-mediated inflammatory diseases (IMIDs). Although Janus kinase inhibitors (JAKi) are an effective treatment for several IMIDs, they have come under scrutiny as a class because of a potential risk of venous thromboembolism and cardiovascular (CV) events, specifically noted with the oral JAKi, tofacitinib, as reported in the ORAL Surveillance Trial of a high CV risk rheumatoid arthritis population. This trial resulted in a black box warning from the Food and Drug Administration and European Medicines Agency regarding risk of venous thromboembolism and CV events that was extended across several types of JAKi (including topical ruxolitinib) when treating IMIDs, leading to considerable controversy. Included is an up-to-date review of the current and rapidly evolving literature on CV risk in patients with IMIDs on JAKi therapy, including identification of potential risk factors for future venous thromboembolism and CV events on JAKi therapy. We suggest a comprehensive, multimodal, and systematic approach for evaluation of CV risk in patients considering taking JAKi and emphasize that cardiologists play an important role in risk stratification and mitigation for patients with high CV risk factors or on long-term JAKi therapies.

P85 Switching from adalimumab originator to biosimilar: a 3-year retrospective cohort analysis

Abstract Biological drugs have revolutionized the treatment of immune-mediated inflammatory diseases. Clinical experience and evidence suggest that biosimilars can be used as safely and effectively as their originator. However, patients’ perceptions of biosimilars are that they are inferior to the originator. Currently, few studies have assessed the tolerability and efficacy of switching from the adalimumab originator to a biosimilar in patients with well-controlled moderate-to-severe psoriasis. Our objective was to describe the clinical experience of switching patients from the adalimumab originator to a biosimilar and that of switching back to the originator for those intolerant to biosimilars. A single-centre, retrospective cohort study was conducted to identify patients with moderate-to-severe psoriasis who had switched from the adalimumab originator (Humira®) to a biosimilar (Amgevita® or Imraldi®) from 2018 to 2022. Patient data were obtained from a combination of patient records and databases, including the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) and the National High Tech Prescribing Hub. Patients were excluded from the study if their treatment duration on an adalimumab biosimilar was &amp;lt; 16 weeks or if they were being treated for an indication other than psoriasis. From 2018 to 2022, 100 patients who switched from the adalimumab originator to a biosimilar were identified. At week 16, 81 patients (81%) maintained their initial switch from the adalimumab originator to biosimilar. Nineteen (19%) patients who were switched to an adalimumab biosimilar were switched back to the originator secondary to adverse events. Maintenance or improvement in baseline Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) was observed in 91% and 90%, respectively, in patients who remained on a biosimilar. For those intolerant to biosimilars, maintenance or improvement in baseline PASI and DLQI was still observed although in fewer patients: 63% and 47%, respectively. Our study demonstrates that drug efficacy was recaptured and adverse events were ameliorated for all patients switched from an adalimumab biosimilar back to the originator. For patients who did not tolerate biosimilar switch, reasons for switching back to the originator mirrored those reported in the literature. All patients who switched back to the originator from a biosimilar recovered from loss of efficiency and the adverse events they had reported. Physicians should be confident in switching patients with well-controlled psoriasis to adalimumab biosimilars. For the small proportion of patients who experienced loss of efficacy or adverse events, all were recaptured by either switching to an alternative adalimumab biosimilar or switching back to the adalimumab originator.

P43 Patient tolerability of adalimumab biosimilar therapy in dermatology and rheumatology: real-world experience from a large tertiary centre

Abstract Adalimumab is widely used in the treatment of immune-mediated inflammatory diseases. It is the highest-spend drug in the National Health Service, costing more than £400 million annually. In 2018, adalimumab biosimilars became available, leading to substantial cost savings. However, patient tolerability of biosimilars remains underexplored. We evaluated the tolerability of adalimumab biosimilar therapy (Idacio®) in patients who were switched from Humira® in a large dermatology and rheumatology tertiary centre. We identified all patients issued with a prescription of Humira by dermatology [psoriasis and hidradenitis suppurativa (HS)] or rheumatology (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and Behçet disease) and analysed the number who switched to Idacio between January 2021 and March 2022. Patient electronic records were reviewed up to October 2022 to identify patients who switched back to the originator product and the documented reason for the switch. The primary outcome was the numbers of patients who were switched back from the biosimilar to the originator product. Of 769 patients issued with a prescription of Humira, 694 were switched to Idacio during the study period. Of these, 134 (19.3%) switched back to the originator product, 102 of whom (76.1%) remained on this during follow-up. The highest proportion of individuals switching back to the originator product was observed in the HS population (26.7%). The most common reasons for switching back were patient-reported loss of disease control (n = 63; 47.0%), injection pain (n = 51; 38.1%) or both (n = 10; 7.5%). The median time to switch back was 197 days (interquartile range 138–280). Of 694 patients prescribed Idacio, 32 (4.6%) were switched to an alternative biologic agent during the study period. Our experience with previous biosimilar switches within rheumatology and dermatology (etanercept, rituximab and infliximab) has resulted in few patients requiring a switch back to the originator. Our data indicate that around one in five patients in our study population switched back to the originator product. The higher proportion of patients citing injection pain may relate to the citrate excipient content or larger injection volume of the biosimilar Idacio. Loss of efficacy with time is well established with adalimumab, in part due to antidrug antibodies, and cannot be specifically attributed to the biosimilar. Switching may alter a patient’s confidence in the drug, which is particularly important when it may be a first-line therapy or the only approved biologic for a condition. Data on switch-back rates for other adalimumab biosimilars is required to understand how generalizable our findings are and the potential economic implications.

Venous and arterial thromboembolic risk of Janus kinase inhibitors: a systematic review with meta-analysis.

Preliminary data led licencing authorities to alert clinicians of an increased venous thrombotic risk associated to the use of Janus kinase (JAK) inhibitors (JAKi). We performed a systematic review to estimate the risk of venous and arterial thrombosis associated to JAKi for the treatment of immune-mediated inflammatory diseases (IMIDs). Randomized controlled trials (RCTs) on JAKi in patients with IMIDs were identified by the MEDLINE and EMBASE databases until October 2021. Risk of bias was assessed according to Cochrane criteria. The beta-binomial model was applied to calculate pooled odds ratio (OR) and corresponding 95% CI. The PROSPERO registration number is CRD42022324143. We have included one phase I, 21 phase II, three phase II-III and 36 phase III RCTs for a total of 19 443 patients in the JAKi group and 6354 in the control group. Thirty-one (unweighted rate 0.16%; 95% CI: 0.10, 0.21) events were reported in the JAKi group and 20 (unweighted rate 0.22%; 95% CI: 0.12, 0.32) in the control group in a mean follow-up of 16.8 weeks. IMID patients treated with JAKi did not have an increased thromboembolic risk compared with those treated with placebo (OR 0.82; 95% CI: 0.43, 1.56). No statistically different results were seen in subanalyses for each investigated IMID, drug and dosage. JAKi do not increase thromboembolic risk compared with placebo in IMID patients enrolled in selected RCTs.

Therapeutic drug monitoring of disease-modifying antirheumatic drugs in circulating leukocytes in immune-mediated inflammatory diseases.

The treatment of immune-mediated inflammatory diseases (IMIDs) is one of the main challenges of modern medicine. Although a number of disease-modifying antirheumatic drugs (DMARDs) are available, there is wide variability in clinical response to treatment among individuals. Therapeutic drug monitoring (TDM) has been proposed to optimize treatment; however, some patients still experience unsatisfactory outcomes, although the blood concentrations of drugs in these patients remain in the therapeutic range. One possible reason for this is that the conventional samples (e.g., whole blood or plasma) used in TDM may not accurately reflect drug concentrations or concentrations of their metabolites at the target site. Hence, more refined TDM approaches to guide clinical decisions related to dose optimization are necessary. Circulating leukocytes or white blood cells have a critical role in driving the inflammatory process. They are recruited to the site of injury, infection and inflammation, and the main target of small molecule DMARDs is within immune cells. Given this, assaying drug concentrations in leukocytes has been proposed to be of possible relevance to the interpretation of outcomes. This review focuses on the clinical implications and challenges of drug monitoring of DMARDs in peripheral blood leukocytes from therapeutic or toxicological perspectives in IMIDs.

Advances in the mechanisms and applications of inhibitory oligodeoxynucleotides against immune-mediated inflammatory diseases.

Inhibitory oligodeoxynucleotides (ODNs) are short single-stranded DNA, which capable of folding into complex structures, enabling them to bind to a large variety of targets. With appropriate modifications, the inhibitory oligodeoxynucleotides exhibited many features of long half-life time, simple production, low toxicity and immunogenicity. In recent years, inhibitory oligodeoxynucleotides have received considerable attention for their potential therapeutic applications in immune-mediated inflammatory diseases (IMIDs). Inhibitory oligodeoxynucleotides could be divided into three categories according to its mechanisms and targets, including antisense ODNs (AS-ODNs), DNA aptamers and immunosuppressive ODNs (iSup ODNs). As a synthetic tool with immunomodulatory activity, it can target RNAs or proteins in a specific way, resulting in the reduction, increase or recovery of protein expression, and then regulate the state of immune activation. More importantly, inhibitory oligodeoxynucleotides have been used to treat immune-mediated inflammatory diseases, including inflammatory disorders and autoimmune diseases. Several inhibitory oligodeoxynucleotide drugs have been developed and approved on the market already. These drugs vary in their chemical structures, action mechanisms and cellular targets, but all of them could be capable of inhibiting excessive inflammatory responses. This review summarized their chemical modifications, action mechanisms and applications of the three kinds of inhibitory oligodeoxynucleotidesin the precise treatment of immune-mediated inflammatory diseases.

Exploring the perspective of patients with immune-mediated inflammatory diseases and care providers on the use of immunomodulatory drugs in infections: an interview study.

Immunomodulatory agents are safe and effective as treatment for various immune-mediated inflammatory diseases (IMIDs), but are associated with a slightly increased infection risk. It is uncertain whether, in the event of an infection, continuation or temporary interruption of immunomodulatory agents leads to better outcomes. Owing to this uncertainty, it is of importance to explore the perspectives of health-care providers (HCPs) and patients on this topic. In this study, we set out to identify and provide an overview of reasons for both treatment strategies. Semi-structured interviews were conducted with HCPs involved in the pharmacological treatment of IMIDs and with IMID patients using one or more immunomodulatory agent. Purposive sampling was used to enrich data variation. Interviews were conducted until data saturation was reached and subsequently analysed using qualitative content analysis. In total, 13 HCPs and 19 IMID patients were interviewed. A wide range of reasons for both treatment strategies were identified, categorized into 10 overarching themes, including IMID characteristics, infection characteristics and the patient-HCP relationship. In this interview study, we identified various reasons for continuation or temporary interruption of immunomodulatory agents during infections for both IMID patients and HCPs. We found overlapping themes, such as IMID characteristics; however, the content and interpretation of these themes might differ between HCPs and patients. Both HCPs and patients mentioned that the decision for a treatment strategy is often about weighing benefits against risks (e.g. infection severity vs disease flare).

The biology of VSIG4: Implications for the treatment of immune-mediated inflammatory diseases and cancer

V-set and immunoglobulin domain containing 4 (VSIG4), a type I transmembrane receptor exclusively expressed in a subset of tissue-resident macrophages, plays a pivotal role in clearing C3-opsonized pathogens and their byproducts from the circulation. VSIG4 maintains immune homeostasis by suppressing the activation of complement pathways or T cells and inducing regulatory T-cell differentiation, thereby inhibiting the development of immune-mediated inflammatory diseases but enhancing cancer progression. Consequently, VSIG4 exhibits a potential therapeutic effect for immune-mediated inflammatory diseases, but also is regarded as a novel target of immune checkpoint inhibition in cancer therapy. Recently, soluble VSIG4, the extracellular domain of VSIG4, shed from the surface of macrophages, has been found to be a biomarker to define macrophage activation-related diseases. This review mainly summarizes recent new findings of VSIG4 in macrophage phagocytosis and immune homeostasis, and discusses its potential diagnostic and therapeutic usage in infection, inflammation, and cancer.