TNF-Alpha Inhibitors and Ustekinumab for the Treatment of Psoriasis: Therapeutic Utility in the Era of IL-17 and IL-23 Inhibitors

Psoriasis is a chronic inflammatory condition for which eleven FDA-approved biologic therapies are approved. Over the past decade, studies have documented the higher efficacy of IL-17 and IL-23 inhibitors for the treatment of psoriasis compared to the TNF-alpha inhibitors and ustekinumab, an IL-12/23 inhibitor. Despite this, there remains an important role for the use of TNF-alpha inhibitors and ustekinumab in the treatment of psoriasis. Here, we review how considerations of infection and malignancy risk, patient demographics, treatment resistance, and comorbidities may make certain TNF-alpha inhibitors or ustekinumab an excellent choice for therapy in particular patient subgroups.

Superficial white matter microstructure affects processing speed in cerebral small vessel disease

White matter hyperintensities (WMH) are a typical feature of cerebral small vessel disease (CSVD). This condition contributes to about 50% of dementias worldwide, a massive health burden in aging. Microstructural alterations in the deep white matter (DWM) have been widely examined in CSVD. However, little is known about abnormalities in the superficial white matter (SWM) and their relevance for processing speed, the main cognitive deficit in CSVD. In this paper, 141 patients with CSVD were studied. Processing speed was assessed by the completion time of the Trail Making Test Part A. White matter abnormalities were assessed by WMH burden (lesion volume on T2-FLAIR) and diffusion MRI, including DTI and free-water (FW) imaging microstructure measures. The results of our study indicate that the superficial white matter may play a particularly important role in cognitive decline in CSVD. SWM imaging measures resulted in a large contribution to processing speed, despite a relatively small WMH burden in the SWM. SWM FW had the strongest association with processing speed among all imaging markers and, unlike the other diffusion MRI measures, significantly increased between two patient subgroups with the lowest WMH burdens (possibly representing early stages of disease). When comparing two patient subgroups with the highest WMH burdens, the involvement of WMH in the SWM was accompanied by significant differences in processing speed and white matter microstructure. Given significant effects of WMH volume and regional FW on processing speed, we performed a mediation analysis. SWM FW was found to fully mediate the association between WMH volume and processing speed, while no mediation effect of DWM FW was observed. Overall, our findings identify SWM abnormalities in CSVD and suggest that the SWM has an important contribution to processing speed. Results indicate that FW in the SWM is a sensitive marker of microstructural changes associated with cognition in CSVD. This study extends the current understanding of CSVD-related dysfunction and suggests that the SWM, as an understudied region, can be a potential target for monitoring pathophysiological processes in future research.

Clusters of Severe Eosinophilic Asthma in a Korean Asthma Cohort

<b><i>Background:</i></b> Targeted therapies have broadened the available treatment options for patients with severe eosinophilic asthma (SEA). However, differences in the magnitude of treatment responses among patients indicate the presence of various underlying pathophysiological processes and patient subgroups. <b><i>Objectives:</i></b> We aimed to describe the characteristics of SEA and identify its patient subgroups. <b><i>Methods:</i></b> Clinical data from the Cohort for Reality and Evolution of Adult Asthma in Korea were analyzed. Cluster analysis was performed among those with SEA using 5 variables, namely, prebronchodilator forced expiratory volume in 1 s, body mass index, age at symptom onset, smoking amount, and blood eosinophil counts. <b><i>Results:</i></b> Patients with SEA showed prevalent sensitization to aeroallergens, decreased lung function, and poor asthma control status. Cluster analysis revealed 3 distinctive subgroups among patients with SEA. Cluster 1 (<i>n</i> = 177) consisted of patients reporting the lowest blood eosinophils (median, 346.8 cells/μL) and modest severe asthma with preserved lung function during the 12-month treatment period. Cluster 2 (<i>n</i> = 42) predominantly included smoking males with severe persistent airway obstruction and moderate eosinophilia (median, 451.8 cells/μL). Lastly, cluster 3 (<i>n</i> = 95) included patients with the most severe asthma, the highest eosinophil levels (median, 817.5 cells/μL), and good treatment response in terms of improved lung function and control status. <b><i>Conclusions:</i></b> Three subgroups were identified in SEA through the cluster analysis. The distinctive features of each cluster may help physicians predict patients who will respond to biologics with greater magnitude of clinical improvement. Further research regarding the underlying pathophysiology and clinical importance of each subgroup is warranted.

Prognostic phenotypes of early-stage lung adenocarcinoma

BackgroundSurvival after curative resection of early-stage lung adenocarcinoma (LUAD) varies and prognostic biomarkers are urgently needed.MethodsLarge-format tissue samples from a prospective cohort of 200 patients with resected LUAD were immunophenotyped for cancer hallmarks TP53, NF1, CD45, PD-1, PCNA, TUNEL, and FVIII, and were followed for median (95%CI)=2.34 (1.71–3.49) years.ResultsUnsupervised hierarchical clustering revealed two patient subgroups with similar clinicopathologic features and genotype, but with markedly different survival: “proliferative” patients (60%) with elevated TP53, NF1, CD45, and PCNA expression had 50% 5-year overall survival while “apoptotic” patients (40%) with high TUNEL had 70% 5-year survival [HR95%CI=2.23 (1.33–3.80); p=0.0069]. Cox regression and machine learning algorithms including random forests built clinically useful models: a score to predict overall survival and a formula and nomogram to predict tumour phenotype. The distinct LUAD phenotypes were validated in TCGA and KMplotter data and showed prognostic power supplementary to IASLC TNM stage and WHO histologic classification.ConclusionsTwo molecular subtypes of LUAD exist and their identification provides important prognostic information.

Using the Symptom Patient Similarity Network to Explore the Difference between the Chinese and Western Medicine Pathways of Ischemic Stroke and its Comorbidities

Background and Objectives. The development of network medicine provides new opportunities for disease research. Ischemic stroke has a high incidence, disability, and recurrence rate, and one of the reasons is that it is often accompanied by other complex diseases, including risk factors, complications, and comorbidities. Network medicine was used to try to analyze the characteristics of IS-related diseases and find out the differences in genetic pathways between Chinese herbs and Western drugs. Methods. Individualized treatment of traditional Chinese medicine (TCM) provides a theoretical basis for the study of the personalized classification of complex diseases. Utilizing the TCM clinical electronic medical records (EMRs) of 7170 in patients with IS, a patient similarity network (PSN) with shared symptoms was constructed. Next, patient subgroups were identified using community detection methods and enrichment analyses were performed. Finally, genetic data of symptoms, herbs, and drugs were used for pathway and GO analysis to explore the characteristics of pathways of subgroups and to compare the similarities and differences in genetic pathways of herbs and drugs from the perspective of molecular pathways of symptoms. Results. We identified 34 patient modules from the PSN, of which 7 modules include 98.48% of the whole cases. The 7 patient subgroups have their own characteristics of risk factors, complications, and comorbidities and the underlying genetic pathways of symptoms, drugs, and herbs. Each subgroup has the largest number of herb pathways. For specific symptom pathways, the number of herb pathways is more than that of drugs. Conclusion. The research of disease classification based on community detection of symptom-shared patient networks is practical; the common molecular pathway of symptoms and herbs reflects the rationality of TCM herbs on symptoms and the wide range of therapeutic targets.

The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges

Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010–2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes.