Machine Learning Model for Predicting Outcomes of Biologic Therapy in Psoriasis

BackgroundBiological agents used for the therapy of psoriasis lose efficacy over time, which leads to discontinuation of the drug. Optimization of long-term biologic treatment is an area of medical need but there are currently no prediction tools for biologic drug discontinuation.ObjectiveTo compare the accuracy of the risk factor-based frequentist statistical model to machine learning to predict the 5-year probability of biologic drug discontinuation.MethodsThe national Danish psoriasis biologic therapy registry, Dermbio, comprising 6,172 treatment series with anti-TNF (Etanercept, Infliximab, Adalimumab), Ustekinumab, Guselkumab and anti-IL17 (Secukinumab and Ixekizumab) in 3,388 unique patients was used as data source. Hazard ratios (HR) were computed for all available predictive factors using Cox regression analysis. Different machine learning (ML) models for the prediction of 5-year risk of drug discontinuation were trained using the 5-fold cross validation technique and using 10 clinical features routinely assessed in psoriasis patients as input variables. Model performance was assessed using the area under the receiver operating characteristic curve (AUC).ResultsThe lowest 5-year risk of discontinuation was associated with therapy with ustekinumab or ixekizumab, male sex and no previous exposure to biologic therapy. The predictive model based on those risk factors had an AUC of 0.61. The best ML model (gradient boosted tree) had an AUC of 0.85.ConclusionsA machine learning-based approach, more than a statistical model, accurately predicts the risk of discontinuation of biologic therapy based on simple patient variables available in clinical practice. ML might be incorporated into clinical decision making.

Management of Moderate and Severe Forms of Psoriasis in Children: New Opportunities of Genetically Engineered Biologic Drugs

The article shows the key role of IL-17 in the psoriasis pathogenesis and the opportunities of its management via monoclonal antibodies product secukinumab. The review of international randomized trials on clinical efficacy and safety of genetically engineered biologic drug secukinumab in children and adolescents with psoriasis is presented. During treatment periods of 12 to 52 weeks, secukinumab has shown high therapeutic efficacy for psoriasis severity and skin lesion areas and has improved quality of life of children and adolescents according to dynamic assessments of PASI, IGA 0/1 mod 2011 indices, CDLQI questionnaire. The safety profile of secukinumab in children is estimated as favorable and comparable to using it in adults.

Intrinsic physicochemical profile of marketed antibody-based biotherapeutics

Feeding biopharma pipelines with biotherapeutic candidates that possess desirable developability profiles can help improve the productivity of biologic drug discovery and development. Here, we have derived an in silico profile by analyzing computed physicochemical descriptors for the variable regions (Fv) found in 77 marketed antibody-based biotherapeutics. Fv regions of these biotherapeutics demonstrate significant diversities in their germlines, complementarity determining region loop lengths, hydrophobicity, and charge distributions. Furthermore, an analysis of 24 physicochemical descriptors, calculated using homology-based molecular models, has yielded five nonredundant descriptors whose distributions represent stability, isoelectric point, and molecular surface characteristics of their Fv regions. Fv regions of candidates from our internal discovery campaigns, human next-generation sequencing repertoires, and those in clinical-stages (CST) were assessed for similarity with the physicochemical profile derived here. The Fv regions in 33% of CST antibodies show physicochemical properties that are dissimilar to currently marketed biotherapeutics. In comparison, physicochemical characteristics of ∼29% of the Fv regions in human antibodies and ∼27% of our internal hits deviated significantly from those of marketed biotherapeutics. The early availability of this information can help guide hit selection, lead identification, and optimization of biotherapeutic candidates. Insights from this work can also help support portfolio risk assessment, in-licensing, and biopharma collaborations.

Outcomes following biosimilar TNF inhibitors use for inflammatory-mediated immune disorders in pregnancy

Background Biosimilar tumour necrosis factor inhibitors (TNFi) are increasingly used to treat inflammatory immune-mediated disorders as they cost less than the originator biologic drug. More women are therefore becoming pregnant on biosimilar TNFi. This is the first paper to explore the safety and efficacy of biosimilar therapies in pregnancy. Methods A retrospective review of clinical data reviewed pregnancy outcomes and inflammatory disease activity in 18 pregnancies where the mother was using a biosimilar TNFi at conception. Results Biosimilar therapy was not associated with congenital abnormalities, preterm birth or other adverse pregnancy outcomes. Stopping biosimilar TNFi in pregnancy was associated with childbirth at an earlier gestation, as well as a flare of inflammatory disease in pregnancy or post-partum. Conclusions Women and clinicians should feel confident in using biosimilar TNFi in early pregnancy, and continuing them through pregnancy to prevent flares in late pregnancy or the early post-partum.

Frailty as a novel predictor of achieving comprehensive disease control (CDC) in rheumatoid arthritis

Background Frailty is a construct recently introduced in the context of inflammatory joint diseases. To date, it is not clear if frailty can act as a negative factor in the achievement of comprehensive disease control (CDC) in patients suffering from rheumatoid arthritis (RA). Aim To verify whether frailty is a factor hindering the achievement of CDC in patients with RA starting a biologic drug. Methods RA patients requiring a treatment with a biologic drug were included. Patients were classified as achieving or not achieving CDC after 12 months of treatment. Patients were classified as non-frail, mildly frail, moderately frail and severely frail according to the Comprehensive Rheumatologic Assessment of Frailty (CRAF). Frailty was tested using the Mann–Whitney or Kruskal-Wallis test for continuous variables and chi-square test or Fisher’s exact test for comparison with categorical variables. A multivariable logistic regression was performed to identify factors associated with prediction of CDC achievers. Results A total of 214 RA patients were followed for 12 months, 14.5% achieved CDC. Eighty-four (39.3%) patients were non-frail, 57 (26.6%) were mildly frail, 14 (6.5%) were moderately frail and 59 (27.6%) were severely frail. The multivariable logistic regression analysis identified the CRAF score at baseline as an independent variable for CDC achievement at 12 months (p = 0.0040). Discussion Frailty is a frequent condition in RA patients and reduces the chances of achieving CDC. Conclusions Frailty, measured by CRAF, reduced the likelihood of CDC achievement in RA patients treated with a biologic agent. Key Points• Frailty is an under-researched condition in rheumatoid arthritis affecting more than 60% of patients.• Frailty is a condition that hinders the achievement of comprehensive disease control after 1 year of treatment with biological drugs in patients with rheumatoid arthritis.

Evaluation of Hypersensitivity Reactions in Pediatric Patients Using Biological Drugs

<b><i>Introduction:</i></b> Biological drugs are currently used for the treatment of chronic inflammatory, autoimmune, and neoplastic diseases. With their expanding indication spectrum and increasing use, hypersensitivity reactions to these drugs are also becoming more frequent. The present study aimed to report the incidence and the features of such reactions in pediatric patients using biologicals for the treatment of various diseases. <b><i>Methods:</i></b> The medical records of pediatric patients treated with biological agents between October 1, 2011 and August 31, 2019 were reviewed and adverse reactions were evaluated retrospectively. <b><i>Results:</i></b> During the study period, 211 patients (116 boys, 55%) used 21 different biological drugs for the treatment of various diseases. Their median age at the time of the first treatment was 139.9 (IQR: 92.2–187.8) months. Hematologic-oncologic diseases were the most common indication for biological therapy (97/211; 46.0%), followed by rheumatologic diseases (82/211; 38.9%). Of the 211 patients, 14 (6.64%) experienced reactions to biological drugs. The most common culprit agent was rituximab (57.1%). Most of the patients (85.7%) had a history of reactions either during the infusion or within 1 h after taking the drug. Five patients underwent desensitization to the culprit drug, while 7 other patients continued treatment with a reduced dose/infusion rate or premedication. Also 1 patient continued to take the drug without any additional treatment. <b><i>Conclusion:</i></b> It was reported that 6.64% of the patients who received biologic drug therapy for various reasons in our hospital had hypersensitivity. The most common culprit agent was rituximab, and most of the reactions were immediate reactions.

Direct and Indirect Impact of COVID-19 for Patients with Immune-Mediated Inflammatory Diseases: A Retrospective Cohort Study

Importance: Since the beginning of the Coronavirus Disease-19 (COVID-19) pandemic, Severe Acute Respiratory Syndrome-CoV-2 (SARS-CoV-2) infection has been a serious challenge for immune-compromised patients with immune-mediated inflammatory diseases (IMIDs). Objective: Our aim was to investigate the impact of COVID-19 in terms of risks of infection, hospitalization and mortality in a cohort of patients with rheumatoid arthritis (RA), psoriasis (PSO) or inflammatory bowel disease (IBD). Furthermore, we studied the impact of SARS-CoV-2 infection on the prescribed drug regimen in these patients. Methods: Through the record linkage between health information systems, a cohort of patients, ≥18 years old, assisted in the Lazio region and who had suffered from immune-mediated inflammatory diseases (RA, PSO, IBD) between 2007 and 2019, was identified. The risk of infection, hospitalization or mortality for COVID-19, was assessed by logistic regression models, and reported in an Odds Ratio (ORs; CI 95%), adjusting for sex, age and the Charlson Comorbidity Index. We also estimated these risks separately by IMID and in the subgroup of prevalent biologic drug users. We investigated deferral of biological treatments in the study population by comparing the prevalence of weekly use of biologicals (2019–2020) before and during the pandemic periods. Findings: Within the 65,230 patients with IMIDs, the cumulative incidence for COVID-19 was 303/10,000 ab. In this cohort of patients, we observed a significantly higher risk of SARS-CoV-2 infection than the general population: OR = 1.17 (95% CI 1.12–1.22). The risk was higher even considering separately each disease and in the subgroup of prevalent biologic drug users. This last subgroup of patients showed a higher risk of death related to COVID-19 (OR 1.89; 95% CI 1.04–3.33) than the general population. However, no differences in terms of risks of hospitalization or death related to COVID-19 were recorded in patients with the IMIDs. Comparing the 2019–2020 prevalence of weekly biological drug treatments in prevalent biologic drug users, we found a decrease (−19.6%) during the lockdown, probably due to pandemic restrictions. Conclusions and Relevance: Patients with IMIDs seem to have a higher risk of SARS-CoV2 infection. However, other than for patients with prevalent biologic drug treatment, no significant differences in terms of hospitalization and mortality were reported compared to the general populations; further investigation is warranted on account of unmeasured confounding. In addition, during the lockdown period, the COVID-19 emergency highlighted a lower use of biologic drugs; this phenomenon requires strict pharmacological monitoring as it could be a proxy of forthcoming long-term clinical progression.

POS1312 DRUG SURVIVAL FOR IL-6 INHIBITOR TOCILIZUMAB: DATA FROM A SINGLE-CENTER OBSERVATION

Background:The efficacy of tocilizumab for treatment patients with systemic juvenile idiopathic arthritis (sJIA) was demonstrated before. We want to describe tocilizumab drug survival based on data from a single-center observation.Objectives:To analyze the drug survival of tocilizumab in patients with sJIA treated at the National Medical Research Center of Children`s health, Moscow, Russia.Methods:Medical records from sJIA patients treated with tocilizumab (TOC) were analyzed retrospectively from the National Medical Research Center of Children`s health, Moscow, Russia.Results:One hundred ninety-two patients presenting with sJIA were included in this observation, with a median age at treatment initiation of 7,2 (interquartile range, IQR 3,9-10,8) years and a median disease duration of 1,9 (IQR 0,4-5,9) years. All patients had been bio-naive. TOC therapy was highly effective in patients with sJIA. At 6 month of follow-up 148/172 (86%) patients achieved inactive disease according the criteria C. Wallace, disease activity persisted in 24/172 (14%) patients. At 1 year of medication 139/150 (92%) patients had inactive disease. We analyzed the reason of TOC withdrawal retrospectively. A total of 82/192 drug withdrawals were performed. TOC was discontinued due to primary ineffectiveness in 4 patients, due to secondary ineffectiveness in 39 patients. 33 patients achieved drug-free remission. Six patients developed side effects that required discontinuation of TOC therapy (4 patients had allergic reactions, 1 patient developed tuberculosis, 1 patient had severe neutropenia). 47/82 patients were switched on other biologic drug: on canakinumab (31), on TNF-inhibitors (11), on rituximab (5). In summary, TOC was canceled in 49/192 (25%) patients due to ineffectiveness or AEs in our cohort.Conclusion:These results demonstrated that TOC is highly effective as the first biologic drug in patients with sJIA. Our observations have shown a good tolerability and survival of the IL-6 inhibitor TOC in patients with sJIA treated in a real-world clinical setting.Disclosure of Interests:None declared