The Role of Inhalant Allergens on the Clinical Manifestations of Atopic Dermatitis.

BACKGROUND: Inhalant allergens provide a source of environmental factors that contribute to the development of clinical symptoms in patients with atopic dermatitis (AD). OBJECTIVE: To review the relationship between inhalant allergens and AD. METHODS: A literature review was conducted using three databases: PubMed/MEDLINE, ClinicalKey, and Web of Science. Search terms, including "atopic dermatitis," "atopic eczema," and "eczema," were used in combination with "inhalant allergen," "inhaled allergen," and "aeroallergen" to identify relevant published manuscripts that highlight the relationship between AD and exposures to inhalant allergens. RESULTS: Fifteen articles were suitable for review. The studies included in the review investigated the effect of inhalant allergens on the clinical manifestations of AD through bronchial provocation, direct skin contact, and allergen sensitization. CONCLUSION: There is a significant relationship between exposures to inhalant allergens and AD. Inhalant allergens may aggravate AD symptoms by either bronchial provocation or direct skin contact. Sensitization of inhalant allergens, mainly house dust mites, follows a specific age-related pattern.

CT109-SN-38, a Novel Antibody-drug Conjugate with Dual Specificity for CEACAM5 and 6, Elicits Potent Killing of Pancreatic Cancer Cells.

BACKGROUND: CEACAM5 and CEACAM6 are glycosylphosphatidylinositol (GPI)- linked members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which are frequently upregulated in epithelial cancers where they contribute to invasion, metastasis, immune evasion, and resistance to anoikis. CT109 is a novel antibody with dual specificity to both CEACAM5 and 6. OBJECTIVES: In this study, we aimed to perform the preclinical characterization of CT109 and antibody- drug conjugate (ADCs) derivatives of CT109, focusing on CT109-SN-38. METHODS: CT109's cognate epitope was characterized by scanning mutagenesis. CT109 specificity and internalization kinetics were assessed by immunoblot and flow cytometry, respectively. Cognate antigen expression prevalence in colorectal cancer and normal tissue arrays was determined by immunohistochemistry. CT109 conjugations were generated by the reaction of reduced CT109 cysteines with maleimide-functionalized payload linkers. In vitro cytotoxic activity of CT109 ADCs was characterized on antigen-positive and negative pancreatic ductal adenocarcinoma cell (PDAC) lines using a luminometric viability assay. In vivo efficacy of CT109-SN-38 was assessed on a PDAC tumor xenograft model at 10 and 25 mg/kg concentrations. RESULTS: CT109 was shown to bind a glycoepitope centered on N309. CT109 is internalized in the CEACAM5+/CEACAM6+ double-positive PDAC line, BxPC-3, with a t1/2 of 2.3 hours. CT109 ADCs elicit a dose and antigen-dependent cytotoxic effect, with CT109-SN-38 exhibiting an IC50 value of 21 nM in BxPC-3 cells. In a BxPC-3 tumor xenograft model, CT109-SN-38 reduced tumor growth and induced regression in 3/10 mice at a concentration 25 mg/kg. CONCLUSION: These data suggest that further preclinical and clinical development of CT109-SN-38 is warranted.

The Effects of Cardiometabolic Comorbidities on Biologic Treatment for Psoriasis with Respect to PASI Scores: A Qualitative Systematic Review.

Objective: Cardiometabolic risk factors have been shown to decrease biologic efficacy in patients treated for inflammatory conditions. The purpose of this systematic review is to provide a qualitative evaluation of studies investigating biologic response among psoriasis patients with cardiometabolic comorbidities. Methods: A comprehensive review was conducted according to the Preferred Reporting Guidelines for Systematic Reviews and Meta-Analysis guidelines to screen for studies including patients with cardiometabolic risk factors receiving biologic therapy for psoriasis. Studies not including a Psoriasis Area and Severity Index (PASI) score to evaluate treatment outcomes were not included. All studies underwent quality/bias analysis using the Methodological Index for Non-Randomized Studies (MINORS) scale. Results: Obesity and Body Mass Index (BMI) were the most studied cardiometabolic risk factors. The majority of the studies reported a lower frequency of achieving PASI75 and PASI90 response with increasing BMI/obesity rates. Diabetes and hypertension showed similar findings but were not studied as frequently. Hyperlipidemia and other lipid disorders were less frequently studied. Conclusion: Relationships between cardiometabolic risk factors and lower frequencies of achieving PASI75/90 exist in current literature. This qualitative systematic review reports evidence of lower PASI75 and PASI90 response rates in the presence of cardiometabolic risk factors.

Proportions of Biologic Discontinuation Among Psoriasis Patients With Metabolic Comorbidities.

Background: Among psoriasis patients, the presence of metabolic comorbidities associates with poorer response to biologics. How the presence of comorbidity impacts treatment patterns with biologics is not fully understood. Methods: Adult patients in the CorEvitas Psoriasis Registry were included if they initiated biologic therapy between 5/2015-12/2019 and had a 6-month follow-up visit. The frequency of biologic discontinuations by 6-months were calculated by metabolic comorbidity status (current obesity and histories of hypertension [HTN], diabetes [DM], and hyperlipidemia [HLD]) for all patients and by drug class (tumor necrosis factor inhibitors [TNFi], interleukin-17i [IL-17i], and IL-23i or IL-12/23i). Results: Among the 2924 participants, discontinuations were more frequent in those with obesity (17%, P < .01) or DM (20%, P < .001) compared to those without these (13% and 14%, respectively). Discontinuations were similar for those with and without histories of HTN or HLD. Frequencies of discontinuation for each biologic class were: TNFi (26%), IL-17i (16%), and IL-23i or IL-12/23i (9%). Among TNFi initiators, the proportions of discontinuations were greater in the presence of obesity (30%, P < .05), DM (34%, P < .05), or HTN (34%, P < .01) compared to those without (22%, 24%, and 22%, respectively). Of the IL-23i or IL-12/23i initiators, discontinuations were more frequent in those with obesity (11%, P < .01) or with DM (13%, P < .05) compared to those without (7% and 8%, respectively). Discontinuations did not statistically differ between comorbidity groups in IL-17i initiators. Conclusion: Comorbid disease status, especially obesity and DM, should be assessed at biologic initiation as it may predict a less optimal clinical outcome.

Cardiometabolic multimorbidity is common among patients with psoriasis and is associated with poorer outcomes compared to those without comorbidity.

BACKGROUND: Associations between cardiometabolic multimorbidity and response to therapy in psoriasis are unknown. OBJECTIVE: Determine the associations of multimorbidity with response to biologic treatment in psoriasis patients. METHODS: CorEvitas Psoriasis Registry participants who initiated biologic therapy and had 6-month follow-up were stratified by 0, 1, 2+ comorbidities (diabetes, hypertension, hyperlipidemia). Adjusted odds ratios (95% CIs) were calculated overall and separately by biologic class (TNFi, IL-17i, IL-12/23i + IL-23i), to assess the likelihood of achieving response for the 1 and 2+ groups vs. 0. RESULTS: Of 2,923 patients, 49.5%, 24.7% and 25.8% reported 0, 1 and 2+ comorbidities, respectively. Overall, likelihood of PASI75 was 18% (OR = 0.82; 95%CI: 0.67, 1.00) and 23% (OR = 0.77; 95%CI: 0.63, 0.96) lower in those with 1 and 2+ comorbidities, respectively, vs. 0. In those who initiated IL-17i, odds of PASI75 and PAS90 were 34% (OR = 0.66; 95%CI: 0.48-0.91) and 35% (OR = 0.65; 95%CI: 0.47-0.91) lower in the 2+ multimorbidity cohort. No significant associations were found among users of TNFi or IL-12/23i + IL-23i groups in the multimorbidity group. LIMITATIONS: Patients may not be representative of all psoriasis patients. CONCLUSION: Multimorbidity in psoriasis may decrease the likelihood of achieving treatment response to biologic therapy and should be considered when discussing treatment expectations with patients.

Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype.

Host defense and inflammation are regulated by the NF-κB essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of NF-κB kinase regulatory subunit gamma (IKBKG) encoding NEMO typically present with immunodeficiency. Here, we characterized a pediatric autoinflammatory syndrome in 3 unrelated male patients with distinct X-linked IKBKG germline mutations that led to overexpression of a NEMO protein isoform lacking the domain encoded by exon 5 (NEMO-Δex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-κB in response to TNF but not TLR3 or RIG-I-like receptor (RLR) stimulation when isoform levels were high. By contrast, T cells, monocytes, and macrophages that expressed NEMO-Δex5 exhibited increased NF-κB activation and IFN production, and blood cells from these patients expressed a strong IFN and NF-κB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-Δex5, promoting type I IFN induction and antiviral responses. These data revealed how IKBKG mutations that lead to alternative splicing of skipping exon 5 cause a clinical phenotype we have named NEMO deleted exon 5 autoinflammatory syndrome (NDAS), distinct from the immune deficiency syndrome resulting from loss-of-function IKBKG mutations.

Physical activity engagement and responses to exercise in plaque psoriasis: a multifactorial investigation of influential factors.

BACKGROUND: Psoriasis may increase the risk of physical inactivity, but few studies have evaluated the etiology. OBJECTIVE: To identify barriers to and predictors of physical activity in psoriasis. METHODS: Twenty individuals with psoriasis (PsO) and 23 controls recorded activity with accelerometers and completed self-paced 20-min treadmill bouts. Questionnaires on self-efficacy for exercise (SEE), pruritus, and dermatology life quality index (DLQI) were completed. Psoriasis severity was measured via body surface area (BSA), psoriasis area and severity index (PASI), and investigator's global assessment (IGA). RESULTS: No differences in moderate-vigorous activity existed between PsO and controls (ANCOVA means: 26 ± 4 versus 27 ± 4 min, p = .802). Relative to controls, PsO selected treadmill speeds that were 13-18% slower and experienced more pruritus while exercising. Among the PsO group, PASI, BSA, IGA, and DLQI showed inverse correlations with vigorous activity (partial rhos= -0.55 to -0.62, p < .05). Likewise, BSA, IGA, DLQI, and pruritus were inversely correlated with footsteps (partial rhos= -0.47 to -0.62, p < .05). SEE was consistently positively correlated with activity levels among PsO (partial rhos ≥0.60 for moderate activity, vigorous activity, and footsteps). CONCLUSION: Individuals with extensive psoriasis and poorer SEE engage in less vigorous activity and take fewer footsteps. Among other factors, pruritus is a novel explanation.

Comorbid obesity and history of diabetes are independently associated with poorer treatment response to biologics at 6 months: A prospective analysis in Corrona Psoriasis Registry.

BACKGROUND: Psoriasis is associated with comorbid systemic metabolic disease. OBJECTIVE: To assess possible associations of comorbid obesity, history of diabetes, hypertension, and hyperlipidemia with response to biologic treatment at 6 months among patients in CorEvitas' Psoriasis Registry. METHODS: Participants included 2924 patients initiating biologic therapy (tumour necrosis factor inhibitors [TNFi], interleukin [IL]-17i, IL-12/23i, or IL-23i) with baseline and 6-month follow-up visits available. Logistic regressions resulted in adjusted odd ratios (OR) and 95% confidence intervals (CI) for achievement of response in select outcomes for those with obesity and history of diabetes, hypertension, and hyperlipidemia relative to those without each. RESULTS: Overall, obesity reduced by 25% to 30% odds of achieving PASI75 (OR, 0.75; 95% CI, 0.64-0.88) and PASI90 (OR, 0.70; 95% CI, 0.59-0.81). History of diabetes reduced odds of achieving PASI75 by 31% (OR, 0.69; 95% CI, 0.56-0.85) and PASI90 by 21% (OR, 0.79; 95% CI, 0.63-0.98). Obesity was associated with lower response to TNFi and IL-17i classes. Independent of obesity, diabetes was associated with poorer outcomes when on IL-17i therapy and hypertension, to a lesser extent, when on the TNFi class. No significant associations were found in the hyperlipidemia group. LIMITATIONS: The study assessed only short-term effectiveness and small sample sizes limited the power to detect differences. CONCLUSION: Assessment of comorbid disease burden is important for improved likelihoods of achieving treatment response with biologics.

Geographic Patterns in Psoriasis: An Observational Study of CorEvitas Psoriasis Registry.

Background: How psoriasis disease characteristics, management, and outcomes each vary across the US is not fully understood. Objective: Assess regional disease characteristics for patients enrolled in CorEvitas Psoriasis Registry, report biologic initiations by class over the period, and evaluate regional outcome data for initiations with 6-month follow-up. Methods: Participants included new biologic initiations in CorEvitas Psoriasis Registry from 2014-2019 categorized into 7 different geographic regions: Northeast, East North Central, Mountain/West North Central, South Atlantic, East South Central, West South Central, and Pacific. Baseline demographics and disease characteristics are described by region. For participants with 6-month follow-up data, we report treatment patterns and treatment outcomes. Results: 7520 biologic initiations from 6320 patients were available. Over time, biologic initiations in most US regions within the Registry resulted in a pattern where IL-17 inhibitors were used most frequently, followed by IL-12/23 and IL-23 inhibitors, and lastly by TNF inhibitors. Baseline disease severity varied among regions with the East South Central reporting the largest proportion (25.1%) of very severe disease by body surface area. Frequencies of metabolic comorbid diseases varied between regions (obesity, diabetes, hyperlipidemia, each P < .001; hypertension P < .019), with the East South Central reporting the largest proportions. Rates of achieving PASI75 and IGA 0/1 varied at 6-months (P = .008 and P = .001, respectively), with the East South Central reporting the lowest frequencies. At 6-months 28.2% of biologic initiations in the East South Central were discontinued, of which 22% had switched to another therapy. Conclusion: Providers should be aware of regional trends in disease characteristics to improve overall care of psoriasis patients.

Psoriasis Severity, Comorbidities, and Treatment Response Differ among Geographic Regions in the United States.

Little is known about how psoriatic disease characteristics and treatment outcomes differ geographically in the United States. Our aim was to explore real-world, geographic variations in the use of biologic classes and outcomes within the Corrona Psoriasis Registry. Patient demographics and disease characteristics were assessed at biologic initiation and at 6 months. Logistic regressions were conducted to evaluate the odds of achieving targeted outcomes for seven United States geographic regions. We examined 737 biologic initiations among 717 patients. IL-17 inhibitors were used most frequently (45%), followed by IL-12‒IL-23 and IL-23 inhibitors (38%) and TNF inhibitors (17%). The proportions of patients with obesity (body mass index > 30) and very severe psoriasis (body surface area > 20) were greatest in the East South Central and West South Central regions. After adjusting for age, sex, race, body mass index, and baseline body surface area, decreased odds of achieving 75% improvement in PASI at 6 months were observed among patients in the East South Central (OR = 0.47, 95% confidence interval = 0.28-0.79, P = 0.004), West South Central (OR = 0.43, 95% confidence interval = 0.22-0.87, P = 0.019), and Pacific (OR = 0.49, 95% confidence interval = 0.28-0.84, P = 0.010) regions compared with those observed among patients in the Northeast. The East South Central and West South Central regions may have the greatest frequencies of very severe disease burden and, along with the Pacific region, may be less likely to achieve targeted response within 6 months of initiating biologic therapy.