Navigating the landscape of SLE treatment: An expert viewpoint on the rationality and limitations of early biologic intervention.

The approval of biologics, namely belimumab and anifrolumab, is being a game-changer in the approach to systemic lupus erythematosus (SLE). Currently we are indeed facing a revolution in the treatment paradigm of SLE, encompassing early combination of biologics with standard treatment in severe manifestations. In this regard, a lively discussion is taking place regarding the better positioning of biologics in the treatment of not necessarily severe, yet refractory and/or disfiguring manifestations which expose patients to worsened quality of life, reduced workability and enhanced risk of organ damage especially related to the misuse of glucocorticoids in the long run. Growing evidence supports the early use of targeted treatments in those patients, including the use of biologics before traditional immunosuppression, to achieve control of disease activity while minimizing treatment-related damage, privileging the timely use of therapeutics selectively impacting on key disease mechanisms in spite of a widespread immunosuppression. Patient profiling on a clinical and endotypical basis is helping in identifying better candidates to targeted drugs. More inflammatory organ involvement including persistent arthritis and infiltrating skin lesions seem likely to respond to anifrolumab, while B-mediated manifestations, a lively serology and a relapsing-remitting SLE course hint at a suitable role for belimumab. This seems at least partially connected to the inner effect of either drug, dampening inflammation through down-regulation of interferon signalling in the case of anifrolumab, while plastically modulating the B cell pool composition and function when coming to belimumab. Nevertheless, the mechanisms of both drugs are immunologically entangled at some extent, thereby requiring careful management especially in patients with longer disease history burdened with mixed manifestations. In this viewpoint we go over pros and cons of anticipatory biologic use in SLE, exploring features linked with better efficacy of either drug and the pathogenic and practical rationale for their positioning before traditional immunosuppression in moderate refractory SLE to be optimally managed in the 21st Century.

Assessment of conflicts of interest in literature on monoclonal antibodies for chronic rhinosinusitis with nasal polyposis using the Open Payments Database.

BACKGROUND: Accurate conflict of interest (COI) information is essential for promoting transparency and trust in research. We aim to assess COI disclosure patterns in monoclonal antibodies (MABs) research for chronic rhinosinusitis with nasal polyposis (CRSwNP) using the Open Payments Database (OPD). METHODS: Studies on FDA-approved MABs for CRSwNP (dupilumab, omalizumab, mepolizumab) published between 2019 and 2021 with at least one US author were identified through PubMed. Industry-reported payments from the manufacturers (Sanofi, Regeneron, Genentech, Novartis, and GlaxoSmithKline) between 2018 and 2021 in OPD's General Payments category were collected. Authors were cross-checked against OPD metadata using a previously published ChatGPT-based algorithm. Additionally, this novel algorithm analyzed COI statements for relevant author‒company specific disclosures, identifying disclosed and undisclosed payments made 3‒15 months prior to publication. RESULTS: A total of 214 unique authors from 76 studies were included. Of 30 articles that received at least one relevant payment, 21 (70%) were found to have an undisclosed COI, with a mean total undisclosed payment of $4890 and a median of $10,331. Fifty-six authors had relevant OPD payments and 40 (71.4%) authors did not declare a potential COI. Interestingly, 158 authors had no relevant payments and 62 (39.2%) declared a potential COI. Author order was not significantly associated with potential under- or over-disclosure. CONCLUSION: This study characterizes COI disclosure patterns in rhinosinusitis-relevant MABs research using a novel automated approach. Given the discrepancy between disclosures and industry-reported payments, our findings suggest a need for improved disclosure education and practices.

Clinical characteristics of patients with a family history of psoriasis: an observational epidemiological study in Chinese Han population.

Introduction: Psoriasis, a chronic inflammatory skin disease, is believed to be influenced by both genetic and environmental factors. Despite this understanding, the clinical epidemiological status of psoriasis patients with a family history of the disease remains uncertain. Methods: In this study, we participated in a multicenter observational epidemiological study involved over 1,000 hospitals and enrolled a total of 5,927 psoriasis patients. These patients were categorized into two groups based on the presence or absence of a family history of psoriasis: family history cases (896) and sporadic cases (5,031). The clinical manifestations of these two groups were analyzed through clinical classification, comorbidities, treatment response, and other relevant factors. Results: The findings of our study indicate that individuals with a family history of psoriasis predisposition exhibit a notably elevated prevalence of psoriatic arthritis compared to those with sporadic occurrences. Moreover, patients with a family history of psoriasis display a more rapid and efficacious response to secukinumab. Additionally, individuals with moderate to severe psoriasis are at a heightened risk of developing cardiovascular and liver diseases in comparison to those with mild psoriasis, with no discernible impact of familial history on the likelihood of comorbidities. Discussion: Our study identified the clinical characteristics of individuals with a familial predisposition to psoriasis, offering novel insights into the management and therapeutic approaches for patients with this condition.

Editor's highlights - October, 2024.

Dermatology has seen significant advancements in understanding and treating complex immune-mediated chronic inflammatory skin conditions such as psoriasis and atopic dermatitis. This editorial highlights five pivotal studies that delve into the real-world effectiveness of biological therapies and the challenges of treating pediatric patients with overlapping dermatological conditions. These studies collectively underscore the need for continued research and treatment approaches in dermatology.

Incidence and risk factors for invasive fungal infections in patients initiating TNF-alpha inhibitors for inflammatory bowel disease and rheumatoid arthritis.

In a commercial claims database analysis, <0.5% of patients with inflammatory bowel disease or rheumatoid arthritis developed an IFI within one year of initiating TNF-alpha therapy. Histoplasmosis was the most common IFI type. Overall IFI incidence varied based on region, underlying conditions, and use of certain immunosuppressive medications.

Efficacy of biologics for eosinophilic otitis media.

BACKGROUND: Eosinophilic otitis media (EOM) is an intractable condition primarily treated with steroids. Recently, biologics targeting IgE or IL-5 have been introduced. OBJECTIVES: This study aimed to evaluate the efficacy of biologics for EOM. MATERIALS AND METHODS: We retrospectively collected data on EOM patients treated from January 2008 to December 2020 from electronic medical records. Patients were classified into the steroid group, treated with systemic or local steroids, and the biologics group, treated with biologics with or without steroids. RESULTS: The otorrhea remission rate was 63.33% in the steroid group, comparable to 58.82% in the biologics group (p = 0.760). Before treatment, the steroid group showed better bone-conduction (BC) thresholds at 0.5 kHz and 1 kHz than the biologics group. Post-treatment, the steroid group improved in air-conduction (AC) threshold and air-bone gap (ABG) at 1 kHz and 2 kHz. The biologics group exhibited stable audiological results. No significant differences were observed post-treatment between the groups, except for the BC threshold at 0.5 kHz, which remained as pre-treatment. CONCLUSIONS AND SIGNIFICANCE: Biologics demonstrated similar efficacy in otorrhea remission as steroids and might help maintain hearing levels. Biologics can be considered for controlling EOM with active otorrhea and reducing systemic steroid use.

Effect of processing and formulation factors on Catalase activity in tablets.

The manufacturing of tablets containing biologics exposes the biologics to thermal and shear stresses, which are likely induce structural changes (e.g., aggregation and denaturation), leading to the loss of their activity. Saccharides often act as stabilizers of proteins in formulations, yet their stabilizing ability throughout solid oral dosage processing, such as tableting, has been barely studied. This work aimed to investigate the effects of formulation and process (tableting and spray-drying) variables on catalase tablets containing dextran, mannitol, and trehalose as potential stabilizers. Non-spray-dried and spray-dried formulations were prepared and tableted (100, 200, and 400 MPa). The enzymatic activity, number of aggregates, reflecting protein aggregation and structure modifications were studied. A principal component analysis was performed to reveal underlying correlations. It was found that tableting and spray-drying had a notable negative effect on the activity and number of aggregates formed in catalase formulations. Overall, dextran and mannitol failed to preserve the catalase activity in any unit operation studied. On the other hand, trehalose was found to preserve the activity during spray-drying but not necessarily during tableting. The study demonstrated that formulation and process variables must be considered and optimized together to preserve the characteristics of catalase throughout processing.

Submicron immunoglobulin particles exhibit FcγRII-dependent toxicity linked to autophagy in TNFα-stimulated endothelial cells.

In intravenous immunoglobulins (IVIG), and some other immunoglobulin products, protein particles have been implicated in adverse events. Role and mechanisms of immunoglobulin particles in vascular adverse effects of blood components and manufactured biologics have not been elucidated. We have developed a model of spherical silica microparticles (SiMPs) of distinct sizes 200-2000 nm coated with different IVIG- or albumin (HSA)-coronas and investigated their effects on cultured human umbilical vein endothelial cells (HUVEC). IVIG products (1-20 mg/mL), bare SiMPs or SiMPs with IVIG-corona, did not display significant toxicity to unstimulated HUVEC. In contrast, in TNFα-stimulated HUVEC, IVIG-SiMPs induced decrease of HUVEC viability compared to HSA-SiMPs, while no toxicity of soluble IVIG was observed. 200 nm IVIG-SiMPs after 24 h treatment further increased ICAM1 (intercellular adhesion molecule 1) and tissue factor surface expression, apoptosis, mammalian target of rapamacin (mTOR)-dependent activation of autophagy, and release of extracellular vesicles, positive for mitophagy markers. Toxic effects of IVIG-SiMPs were most prominent for 200 nm SiMPs and decreased with larger SiMP size. Using blocking antibodies, toxicity of IVIG-SiMPs was found dependent on FcγRII receptor expression on HUVEC, which increased after TNFα-stimulation. Similar results were observed with different IVIG products and research grade IgG preparations. In conclusion, submicron particles with immunoglobulin corona induced size-dependent toxicity in TNFα-stimulated HUVEC via FcγRII receptors, associated with apoptosis and mTOR-dependent activation of autophagy. Testing of IVIG toxicity in endothelial cells prestimulated with proinflammatory cytokines is relevant to clinical conditions. Our results warrant further studies on endothelial toxicity of sub-visible immunoglobulin particles.

Severe Eosinophilic Asthma or Eosinophilic Granulomatosis with Polyangitis: potential biomarkers for novel diagnostic strategies.

BACKGROUND: Severe Eosinophilic Asthma (SEA) may be the prodromal phase of Eosinophilic Granulomatosis with Polyangiitis (EGPA). Nevertheless, few studies have tried to recognize EGPA in the early stages of the disease. OBJECTIVES: To identify a panel of clinical and biological markers to detect which severe asthmatic patient might be considered in a prodromal phase of EGPA and crafting a strategy for diagnostic decision-making. METHODS: 30 patients with EGPA and 49 with SEA were enrolled. A complete pulmonary, ear, nose and Throat (ENT) and rheumatologic assessment were made. Blood (eosinophil count, eosinophilic cationic protein-ECP, IL5, IL4, total-IgE, IgG4, anti-neutrophil cytoplasmic antibody (ANCA), sputum (eosinophils count, periostin, IL8 and GMCSF) and nasal smear (eosinophilia) biomarkers were assessed. Asthma Control Test, Short Form-36, SinoNasalOutcome Test-22, and Asthma Quality of Life Questionnaire were also used. RESULTS: SEA patients had poorer asthma control (p<0.001) and higher level of sputum eosinophils (p<0.002) while EGPA patients reported higher levels of blood eosinophils in the past. Sputum GMCSF was the only biomarker significantly increased in EGPA patients compared with SEA (p<0.0001). Among SEA patients, those with some suggestive but not diagnostic criteria of EGPA, particularly tissue eosinophilic infiltrates, presented higher levels of sputum GMCSF (p<0.0005), blood and sputum eosinophils (p<0.0006, p<0.011) in comparison with the other patients. CONCLUSION: Sputum GMCSF and eosinophils might be useful biomarkers to support early diagnosis and treatment choices in SEA patients, suspected of having EGPA.

Comparative Efficacy of Biologics and Small Molecule Therapies in Improving Patient-Reported Outcomes in Ulcerative Colitis: Systematic Review and Network Meta-Analysis.

BACKGROUND: Ulcerative colitis (UC) is a chronic disorder with a considerable negative impact on health-related quality of life (HRQoL), which has been recently recognized as an important treatment target. The purpose of this study is to compare the efficacy of different biologics and small molecule therapies in achieving better patient-reported outcomes and HRQoL in patients with UC. METHODS: We performed a systematic review and network meta-analysis of the EMBASE, MEDLINE, and Cochrane Central databases from inception until February 1, 2024. The primary endpoint was clinical remission in the patient-reported outcome (PRO-2) score in UC patients who were treated with different biologics or small molecules during induction and maintenance phases. PRO-2 score is the sum of both stool frequency and rectal bleeding subscores. The secondary outcome was improvement of HRQoL defined as an increase in Inflammatory Bowel Disease Questionnaire score of ≥16 points from baseline or any change in total score from baseline. A random effects model was used, and outcomes were reported as odds ratio with 95% confidence interval. Interventions were ranked per the SUCRA (surface under the cumulative ranking curve) score. RESULTS: A total of 54 studies were included in the primary outcome analysis and 15 studies were included in the secondary outcome analysis. The primary analysis showed that during the induction phase all of included drugs were better than placebo in improving the PRO-2 score. Interestingly, upadacitinib was found to be superior to most medications in improving PRO-2 scores. The secondary analysis showed that guselkumab ranked first in the improvement of the Inflammatory Bowel Disease Questionnaire score, followed by upadacitinib during the induction phase. CONCLUSION: Upadacitinib ranked first in PRO-2 clinical remission during the induction and maintenance phases. Guselkumab, mirikizumab, tofacitinib, and upadacitinib were the only novel medications that were superior to placebo in improving HRQoL in UC, with guselkumab ranking the highest, followed by tofacitinib and upadacitinib. During maintenance of remission, tofacitinib ranked highest in improving HRQoL.

Patient-reported outcome (PRO-2) and disease impact on health-related quality of life (HRQoL) have been recognized as important treatment targets in ulcerative colitis. In this systematic review and network meta-analysis, we compared different biologics and small molecules in achieving these outcomes. We found that upadacitinib ranked first in PRO-2 clinical remission during induction and maintenance phases. Guselkumab, tofacitinib, and upadacitinib were the only novel medications that were superior to placebo in improving HRQoL during induction in ulcerative colitis, with guselkumab ranking the highest, followed by tofacitinib and upadacitinib. During maintenance of remission, tofacitinib ranked highest in improving HRQoL.

Production and characterization of novel Anti-HIV Fc-fusion proteins in plant-based systems: Nicotiana benthamiana & tobacco BY-2 cell suspension.

Multifunctional anti-HIV Fc-fusion proteins aim to tackle HIV efficiently through multiple modes of action. Although results have been promising, these recombinant proteins are hard to produce. This study explored the production and characterization of anti-HIV Fc-fusion proteins in plant-based systems, specifically Nicotiana benthamiana plants and tobacco BY-2 cell suspension. Fc-fusion protein expression in plants was optimized by incorporating codon optimization, ER retention signals, and hydrophobin fusion elements. Successful transient protein expression was achieved in N. benthamiana, with notable improvements in expression levels achieved through N-terminal hydrophobin fusion and ER retention signals. Stable expression in tobacco BY-2 resulted in varying accumulation levels being at highest 2.2.mg/g DW. The inclusion of hydrophobin significantly enhanced accumulation, providing potential benefits for downstream processing. Mass spectrometry analysis confirmed the presence of the ER retention signal and of N-glycans. Functional characterization revealed strong binding to CD64 and CD16a receptors, the latter being important for antibody-dependent cellular cytotoxicity (ADCC). Interaction with HIV antigens indicated potential neutralization capabilities. In conclusion, this research highlights the potential of plant-based systems for producing functional anti-HIV Fc-fusion proteins, offering a promising avenue for the development of these novel HIV therapies.

Comprehensive evaluation of disulfidptosis in intestinal immunity and biologic therapy response in Ulcerative Colitis.

Objective: Ulcerative Colitis (UC) manifests as a chronic inflammatory condition of the intestines, marked by ongoing immune system dysregulation. Disulfidptosis, a newly identified cell death mechanism, is intimately linked to the onset and advancement of inflammation. However, the role of disulfidptosis in UC remains unclear. Methods: We screened differentially expressed genes (DEGs) associated with disulfidptosis in multiple UC datasets, narrowed down the target gene number using lasso regression, and conducted immune infiltration analysis and constructed a clinical diagnostic model. Additionally, we explored the association between disulfidptosis-related key genes and disease remission in UC patients receiving biologic therapy. Finally, we confirmed the expression of key genes in FHC cells and UC tissue samples. Results: In the differential analysis, we identified 20 DEGs associated with disulfidptosis. Immune infiltration results revealed that five genes (PDLIM1, SLC7A11, MYH10, NUBPL, OXSM) exhibited strong correlations with immune cells and pathways. Using GO, KEGG and WGCNA analyses, we discovered that gene modules highly correlated with disulfidptosis-related gene expression were significantly enriched in inflammation-related pathways. Additionally, we developed a nomogram based on these five immune-related disulfidptosis genes for UC diagnosis, showing robust diagnostic capability and clinical efficacy. Kaplan-Meier survival analysis revealed a significant link between changes in the expression levels of these cell genes and disease remission in UC patients receiving biologic therapy. In line with previous studies, similar expression changes of the target gene were seen in both UC cell models and tissue samples. Conclusions: This study utilized bioinformatic analysis and machine learning to identify and analyze features associated with disulfidptosis in multiple UC datasets. This enhances our comprehension of the role disulfidptosis plays in intestinal immunity and inflammation in UC, providing new perspectives for developing innovative treatments for UC.

Progression of Quality of Life in Patients with Plaque Psoriasis Who Achieved Three or More Years of Complete Skin Clearance with Guselkumab Treatment: a Post hoc Analysis of the VOYAGE 1 Clinical Trial.

INTRODUCTION: The interleukin-23p19 subunit inhibitor, guselkumab, has demonstrated improvements in clinical and patient-reported outcome (PRO) measures in patients with moderate-to-severe psoriasis. Understanding the relationship among clinical response, PRO measures and baseline characteristics could help clinicians individualize treatment plans. The objective of this analysis was to examine changes in signs, symptoms and quality-of-life (QoL) PRO measures in patients who maintained complete skin clearance through ≥ 3 years in the phase 3 VOYAGE 1 trial. METHODS: A descriptive post hoc analysis of data from VOYAGE 1 was conducted to compare baseline characteristics of patients who maintained complete skin clearance (Psoriasis Area and Severity Index [PASI] = 0 for ≥ 156 consecutive weeks) versus patients who did not. Mean scores for individual domains of the Dermatology Life Quality Index (DLQI) and Psoriasis Symptom and Sign Diary (PSSD) were evaluated in patients who maintained complete skin clearance, and baseline characteristics of patients who achieved PRO scores of DLQI = 0/1 and PSSD = 0 were compared with those who did not. RESULTS: Of the 329 patients included in this post hoc analysis, 73 (22.2%) maintained PASI = 0 for ≥ 156 weeks. This group had a numerically lower proportion of patients at baseline with obesity, depression or previous biologic treatment and a higher proportion who had never smoked. Patients who maintained PASI = 0 generally achieved positive DLQI and PSSD outcomes, though some impact of residual disease was observed, largely related to the DLQI "Symptoms and feelings" sub-scale and PSSD components "Dryness," "Redness" and "Itch." Patients reporting continued disease impact (despite sustaining PASI = 0) had greater disease severity at baseline versus those achieving DLQI = 0/1 and PSSD = 0. CONCLUSION: Clinical measures alone do not capture the full patient experience. While both QoL and clinical symptoms are responsive to highly effective treatment, a subset of patients with complete clinical response is still impacted by their psoriasis. Further investigation into this population is warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02207231.

General quasi-equilibrium multivalent binding model to study diverse and complex drug-receptor interactions of biologics.

Pharmacokinetics and pharmacodynamics of many biologics are influenced by their complex binding to biological receptors. Biologics consist of diverse groups of molecules with different binding kinetics to its receptors including IgG with simple one-to-one drug receptor bindings, bispecific antibody (BsAb) that binds to two different receptors, and antibodies that can bind to six or more identical receptors. As the binding process is typically much faster than elimination (or internalization) and distribution processes, quasi-equilibrium (QE) binding models are commonly used to describe drug-receptor binding kinetics of biologics. However, no general QE modeling framework is available to describe complex binding kinetics for diverse classes of biologics. In this paper, we describe novel approaches of using differential algebraic equations (DAE) to solve three QE multivalent drug-receptor binding (QEMB) models. The first example describes the binding kinetics of three-body equilibria of BsAb that binds to 2 different receptors for trimer formation. The second example models an engineered IgG variant (Multabody) that can bind to 24 identical target receptors. The third example describes an IgG with modified neonatal Fc receptor (FcRn) binding affinity that competes for the same FcRn receptor as endogenous IgG. The model parameter estimates were obtained by fitting the model to all data simultaneously. The models allowed us to study potential roles of cooperative binding on bell-shaped drug exposure-response relationships of BsAb, and concentration-depended distribution of different drug-receptor complexes for Multabody. This DAE-based QEMB model platform can serve as an important tool to better understand complex binding kinetics of diverse classes of biologics.

Tralokinumab for the Treatment of Adult Atopic Dermatitis in Special Populations.

Introduction: Even if mild forms of atopic dermatitis (AD) are usually well controlled with topical prescription drugs and emollients, the management of severe forms of the disease may be challenging, especially in special populations (SPs). These patients include groups of disadvantaged people (elderly, patients with disabilities and serious medical conditions) who are usually excluded from clinical trials. As a consequence, most of the data about the efficacy and safety of a drug in these patients derives from post-marketing experiences. In this context, the aim of our study was to retrospectively investigate the effectiveness and safety of tralokinumab in the management of AD in SPs. Methods: A 24-weeks retrospective, dual-center study was performed enrolling patients with a diagnosis of moderate-to-severe AD undergoing treatment with tralokinumab at labelled dosage. Disease severity was assessed using Eczema Area Severity Index (EASI), Pruritus-Numerical Rating Scale (P-NRS), and Dermatology Life Quality Index (DLQI) score at baseline and after 4 weeks (W4), W16, and W24. Adverse events (AEs) were monitored at the same timepoints. Statistical significance of clinical improvement (EASI, P-NRS, DLQI) at week 4, week 16, and week 24 as compared with baseline was evaluated by using Student's t-test, considering significant a p-value <0.05. Results: Our study enrolling 27 SPs patients showed a significant improvement in EASI and P-NRS since week 4, continuing to improve up to week 24. Similarly, DLQI significantly decreases at each timepoint as compared with baseline. Finally, no AEs were reported during the study period. Of interest, our cohort included oncologic patients, a patient with a history of severe infection, as well as subjects affected by severe neurological, psychiatric, pulmonary, and/or cardiovascular disease. Discussion: Our experience showed that tralokinumab is effective and safe in elderly patients and subjects affected by severe comorbidities.

The Efficacy and Safety of Biosimilars in Hidradenitis Suppurativa: A Comprehensive Review.

Hidradenitis Suppurativa (HS), also known as Acne Inversa, is a chronic, recurrent inflammatory skin condition primarily affecting apocrine gland-bearing areas, such as the axilla and groin. Characterized by painful nodules, abscesses, and scarring, and has a profound psychological impact on patients. Current treatments aim to manage symptoms and prevent new lesions with a combination of non-pharmacological and pharmacological approaches. Emerging biosimilars, which replicate the efficacy and safety profiles of known biologics at a lower cost, offer new options for treating this debilitating cutaneous disorder. The review summarizes recent studies to explain the role of biosimilars in HS, emphasizing their potential to expand effective treatment options.

Risk factors for interstitial lung disease in rheumatoid arthritis: a cohort study from the KOBIO registry.

Background: Interstitial lung disease (ILD) is a critical extra-articular manifestation of rheumatoid arthritis (RA). However, little is known about the risk factors of RA-ILD. Objectives: Here, we examined the effect of demographic, clinical, therapeutic, and environmental factors on the incidence of ILD in RA patients using the Korean College of Rheumatology Biologics and Targeted Therapy (KOBIO) registry. Design: We used data from the KOBIO registry, a multi-center, prospective, observational cohort that included RA patients in South Korea. Methods: RA patients who used biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) or conventional synthetic (cs)DMARDs, and were enrolled in the KOBIO registry, were examined. Demographic, clinical, and radiographic characteristics, as well as medications, were recorded at baseline and annually thereafter. Kaplan-Meier curves and the log-rank test were used to compare the incidence of ILD between RA patients taking different b/tsDMARDs. Hazard ratios (HRs) were calculated by Cox regression analyses. Results: In total, 2492 patients (1967 in the b/tsDMARDs group and 525 in the csDMARDs group) were analyzed. The b/tsDMARDs group showed longer disease duration, higher erythrocyte sedimentation rate/C-reactive protein, and higher disease activity score-28 (DAS28) than the csDMARDs group. The incidence of ILD was significantly higher in those taking tumor necrosis factor inhibitors and abatacept than in those taking csDMARDs (log ranked p < 0.001). Multivariate Cox regression analysis identified older age (HR = 1.057, p = 0.001), male sex (HR = 2.824, p = 0.007), time-averaged DAS28 (HR = 2.241, p < 0.001), and rheumatoid factor titer (HR = 1.009, p = 0.007) as having a significantly increased HR for ILD occurrence. Conclusion: ILD is a rare but critical extra-articular symptom of RA patients. Therefore, RA patients with the above risk factors should be monitored carefully for ILD development.

Limited predictive value of the gut microbiome and metabolome for response to biological therapy in inflammatory bowel disease.

Emerging evidence suggests the gut microbiome's potential in predicting response to biologic treatments in patients with inflammatory bowel disease (IBD). In this prospective study, we aimed to predict treatment response to vedolizumab and ustekinumab, integrating clinical data, gut microbiome profiles based on metagenomic sequencing, and untargeted fecal metabolomics. We aimed to identify predictive biomarkers and attempted to replicate microbiome-based signals from previous studies. We found that the predictive utility of the gut microbiome and fecal metabolites for treatment response was marginal compared to clinical features alone. Testing our identified microbial ratios in an external cohort reinforced the lack of predictive power of the microbiome. Additionally, we could not confirm previously published predictive signals observed in similar sized cohorts. Overall, these findings highlight the importance of external validation and larger sample sizes, to better understand the microbiome's impact on therapy outcomes in the setting of biologicals in IBD before potential clinical implementation.