Guselkumab-Treated Patients with Plaque Psoriasis Who Achieved Complete Skin Clearance for ≥ 156 Consecutive Weeks: A Post-Hoc Analysis From the VOYAGE 1 Clinical Trial.

BACKGROUND: Treatment of moderate-to-severe plaque psoriasis with biologics, such as guselkumab, has demonstrated greater efficacy over traditional non-biologic treatments. However, given patient diversity, greater understanding of the relationship between patient characteristics, positive clinical outcomes, and long-term response to biologics is crucial for optimizing treatment choices. MATERIALS AND METHODS: This post-hoc analysis of the 5-year VOYAGE 1 clinical trial compares baseline characteristics of patients maintaining a Psoriasis Area and Severity Index (PASI) score of 0 at all visits for ≥ 156 consecutive weeks (PASI = 0 group) with those that never achieve PASI = 0 (comparator group), using descriptive statistics and a multiple logistic regression model. Guselkumab plasma trough concentrations in both response groups were assessed from Weeks 4-156. RESULTS: Of patients who started guselkumab treatment at Week 0 or at Week 16 after switching from placebo, 22.7% (112/494) maintained PASI = 0 for ≥ 156 consecutive weeks. Numerical differences in baseline characteristics, including age, obesity, diabetes, PASI score, disease duration, smoking status, and psoriatic arthritis comorbidity, were identified between the PASI = 0 group and comparator group. Plasma guselkumab levels were consistently higher in the PASI = 0 group. Multiple logistic regression analysis revealed absence of diabetes, lower Dermatology Life Quality Index score at baseline, and higher Week 4 guselkumab plasma concentration as significantly (p < 0.05) associated with the PASI = 0 group. CONCLUSION: A substantial (22.7%) number of guselkumab-treated patients in the VOYAGE 1 clinical trial maintained complete skin clearance for a consecutive period of ≥ 156 weeks. Factors associated with this outcome may suggest clinical benefits of holistic treatment approaches. TRIAL REGISTRATION: NCT02207231.

Challenges in Noninvasive Skin Biomarker Measurements in Daily Practice: A Longitudinal Study on Skin Surface Protein Detection by the Transdermal Analysis Patch in Pediatric Psoriasis.

INTRODUCTION: Skin surface proteins are potential biomarkers in psoriasis and can be measured noninvasively with the transdermal analysis patch (TAP). This study aimed to assess markers measured by TAP over time in daily clinical practice, explore their correlation with disease severity in pediatric psoriasis, and compare the TAP and tape stripping detection capability. METHODS: In this prospective observational daily clinical practice study, pediatric psoriasis patients (aged >5 to <18 years) were followed during 1 year. At each visit, TAPs were applied to lesional (n = 2), peri-lesional (n = 2), and non-lesional (n = 1) sites. Post-lesional skin was sampled if all lesions on the arms, legs, or trunk cleared. Treatment and psoriasis severity data were collected. IL-1RA, hBD-2, IL-1α, IL-8, VEGF, CXCL-1/2, CCL-27, IL-23, hBD-1, IL-22, IL-17A, KLK-5, and IL-4 levels were quantified by spot-ELISA. For the statistical analysis, Wilcoxon signed rank tests, Mann-Whitney U tests, and Spearman correlations were used. Detection capability of the TAP was compared to tape stripping in a separate cohort of adult psoriasis patients. RESULTS: 32 patients (median age 15.0 years, median Psoriasis Area and Severity Index [PASI] 5.2) were followed for a mean of 11.3 (±3.4) months with a total of 104 visits. In lesional skin (n = 197), significantly higher IL-1RA, hBD-2, IL-8, VEGF, CXCL-1/2, IL-23, hBD-1, IL-22, CCL-27, and IL-17A levels were found compared to non-lesional skin (n = 104), while IL-1α was higher in non-lesional skin. Marker levels were highly variable over time and did not correlate with disease severity measured by PASI or SUM scores. Comparison of the TAP and tape strip detection capability in adult psoriasis patients (n = 10) showed that lesional hBD-2, IL1-α, IL-8, and VEGF and non-lesional IL-1RA, hBD-2, IL-8, and VEGF were more frequently detected in tape extracts than TAPs. CONCLUSION: Due to the lack of correlation with clinical disease severity and the current detection capability of the markers measured by TAP in psoriasis, its use in regular practice is still a bridge too far.

Safety Assessment of Conventional and Biological Systemic Therapy in Older Adults with Psoriasis, a Real-world Multicentre Cohort Study.

Optimal selection of systemic therapy in older adults with psoriasis can be challenging, due to sparse evidence-based guidance. This multicentre retrospective study investigated the safety of systemic therapy with causality assessment in a real-world cohort of older adults (≥ 65 years) with psoriasis. Data from 6 hospitals on (serious) adverse events were collected, causality assessment performed and incidence rate ratios calculated. Potential predictors for adverse events-occurrence were studied using multivariable logistic regression analysis. In total, 117 patients with 176 treatment episodes and 390 patient-years were included, comprising 115 (65.3%) and 61 (34.7%) treatment episodes with conventional systemic therapy and biologics/apremilast, respectively. After causality assessment, 232 of 319 (72.7%) adverse events remained and were analysed further, including 12 serious adverse events. No significant differences in incidence rate ratios were found between the systemic treatment types. In regression analysis, increasing age was associated with causality assessed adverse events-occurrence (odds ratio 1.195; p=0.022). Comorbidity, polypharmacy, and treatment type were not associated with causality assessed adverse events-occurrence. In conclusion, increasing age was associated with a higher causality assessed adverse events-occurrence. Causality assessed serious adverse events were rare, reversible and/or manageable in clinical practice. In conclusion, the safety profile of systemic antipsoriatic therapy within this population is reassuring.

Immunological Effects of Anti‒IL-17/12/23 Therapy in Patients with Psoriasis Complicated by Candida Infections.

Biologics that block the T helper (Th) 17 pathway are very effective in the treatment of psoriasis and other inflammatory diseases. However, IL-17 is also crucial for antifungal host defense, and clinical trial data suggest an increase in the incidence of Candida infections during IL-17 inhibitor (IL-17i) therapy. We investigated the innate and adaptive immune responses of patients with psoriasis with a history of skin and/or mucosal candidiasis during IL-17i or IL-12/23 inhibitor therapy, comparing those responses with those of healthy controls. Patients with psoriasis with IL-17i showed significantly lower CD4+Th1-like (CCR6‒CXCR3+CCR4‒) and Th1 Th17-like (CD4+CCR6+CXCR3+CCR4‒) cell percentages. Patient cells stimulated with Candida albicans produced significantly lower IL-6 in the IL-12/23 inhibitor group and IL-1ß in the IL-17i group, whereas the release of TNF-α and ROS was similar between patients and controls. IFN-γ and IL-10 production in response to several stimuli after 7 days was particularly decreased in patients receiving IL-17i therapy. Finally, after stimulation with the polarizing cytokines IL-1ß and IL-23, the Th17 cytokine response was significantly lower in the IL-17i patient group. These innate and adaptive immune response defects can diminish antifungal host immune response and thereby increase susceptibility to candidiasis in patients treated with IL-17i or IL-12/23 inhibitor.

The Effect of Lifestyle Changes on Disease Severity and Quality of Life in Patients with Plaque Psoriasis: A Narrative Review.

Objective: To evaluate the effect of lifestyle changes on the severity of psoriasis and the quality of life in patients with psoriasis. Methods: For this narrative review, PubMed, Embase and ClinicalTrials.gov were searched for lifestyle intervention studies with an intervention duration of at least 12 weeks. Results: Thirty-four intervention studies were included. Most studies performed interventions in the diet of patients with psoriasis (n=9), or added supplements to the diet (n=18). Three studies comprised relaxation techniques and four studies combined relaxation or stress-reducing techniques with an educational program or exercise. No interventional studies were carried out regarding smoking, alcohol and sleep. Especially dietary and relaxation interventions showed promising results with respect to psoriasis severity and dermatology-related QoL, respectively. Regarding dietary supplements, the three largest studies investigating fish oil or vitamin D did not show significant effects. Conclusion: There is some evidence that dietary and relaxation interventions could be promising with respect to psoriasis severity and dermatology-related QoL, respectively. Furthermore, our review identified important gaps in psoriasis lifestyle research regarding study design and reporting of outcomes.

Direct Comparison of Real-world Effectiveness of Biologics for Psoriasis using Absolute and Relative Psoriasis Area and Severity Index Scores in a Prospective Multicentre Cohort.

Real-world evidence, directly comparing the effectiveness of interleukin (IL)17-inhibitors, IL23-inhibitors, tumour necrosis factor alpha (TNF-α)-inhibitors and an IL12/23-inhibitor in psoriasis, is scarce. The aim of this study was to directly compare the first-year effectiveness of biologic therapies for psoriasis, corrected for confounders. This prospective, multicentre cohort study assessed BioCAPTURE data on etanercept, adalimumab, ustekinumab, secukinumab, ixekizumab, and guselkumab in 1,080 treatment episodes of 700 patients with psoriasis. The course of the mean absolute Psoriasis Area and Severity Index (PASI) and the proportion of patients who achieved PASI90/PASI75 were compared using linear mixed models and mixed logistic regression models respectively, corrected for baseline PASI, biologic naivety, and weight. Patients treated with adalimumab, ustekinumab, secukinumab, ixekizumab, or guselkumab all had a significantly lower mean PASI after 12 months compared with etanercept, and significantly higher overall odds of reaching PASI90 than those treated with etanercept. Patients treated with ixekizumab or guselkumab also had higher probabilities of reaching PASI90 than adalimumab, ustekinumab, and secukinumab. Relative to randomized controlled trials, the proportions of patients who reached PASI90/75 were lower in this real-world study.

Global Risk of Bacterial Skin Infections and Herpesviridae Infections with Ustekinumab, Secukinumab, and Tumour Necrosis Factor-alpha Inhibitors: Spontaneous Reports of Adverse Drug Reactions from the World Health Organization Pharmacovigilance Center.

Genetic defects in interleukin-12/23/17 immunity are associated with an increased risk of Staphylococcus aureus and herpesvirus skin infections. This study analysed spontaneous safety reports from the WHO Pharmacovigilance Center of bacterial skin or herpesvirus infections associated with secukinumab, ustekinumab and tumour necrosis factor-α inhibitors. Associations found in disproportionality analyses were expressed as reporting odds ratios (ROR). For bacterial skin infections, ustekinumab showed the strongest association (ROR 6.09; 95% confidence interval (95% CI) 5.44-6.81), and, among the tumour necrosis factor-α inhibitors, infliximab showed the strongest association (ROR 4.18; 95% CI 3.97-4.40). Risk was comparable between infliximab and secukinumab (ROR 3.51; 95% CI 3.00-4.09). Secukinumab showed the strongest association with herpes simplex infection (ROR 4.80; 95% CI 3.78-6.10). All biologics were equally associated with herpes zoster. Infliximab was the only biologic associated with cytomegalovirus infection (ROR 5.66; 95% CI 5.08-6.31) and had the strongest association with Epstein-Barr virus infection (ROR 6.90; 95% CI 6.03-7.90). All biologics evaluated were positively associated with bacterial skin infections, herpes simplex, and herpes zoster, compared with all other drugs in the WHO database for which individual case safety reports were collected. The possibility of under-reporting, reporting bias and difference in causality assessment between countries and reporters must be taken into account when interpreting the results of disproportionality analyses.

Value of reflectance confocal microscopy for the monitoring of rosacea during treatment with topical ivermectin.

BACKGROUND: Reflectance confocal microscopy (RCM) enables noninvasive Demodex mite detection in rosacea. Objective scoring of rosacea severity is currently lacking. OBJECTIVES: To determine the value of RCM for monitoring Demodex, inflammation and vascular parameters in rosacea during treatment. METHODS: In 20 rosacea patients, clinical and RCM examination were performed before, during, and 12 weeks after a 16-week treatment course with topical ivermectin. Using RCM, number of mites and inflammatory cells, epidermal thickness, and vascular density and diameter were measured. RCM features were correlated with clinical assessment. RESULTS: Treatment resulted in clinical reduction of inflammatory lesions. Mites were detected in 80% of patients at baseline, 30% at week 16, and 63% at week 28. The number of mites reduced significantly during treatment, but no changes in inflammatory cells, epidermal thickness or vascular parameters were observed. Correlation between number of inflammatory lesions and mites was low. None of the RCM variables were significant predictors for clinical success. CONCLUSIONS: RCM enables anti-inflammatory effect monitoring of topical ivermectin by determining mite presence. Quantifying exact mite number, and inflammatory and vascular characteristics is challenging due to device limitations. In its current form, RCM seems of limited value for noninvasive follow-up of rosacea in clinical practice.

Predictors of surgical treatment burden, outcomes, and overall survival in older adults with basal cell carcinoma: Results from the prospective, multicenter BATOA cohort.

BACKGROUND: Incorporating patient-related factors associated with treatment outcomes could improve personalized care in older patients with basal cell carcinoma (BCC). OBJECTIVE: To evaluate and identify predictors of treatment burden, treatment outcomes, and overall survival in patients aged ≥70 years, surgically treated for BCC in the head and neck area. METHODS: The data from the prospective, multicenter Basal Cell Carcinoma Treatment in Older Adults (BATOA) cohort study were extracted to evaluate the experienced treatment burden (visual analog scale, 0-10 cm; lower scores indicating higher treatment burden), treatment outcomes, and mortality. RESULTS: A total of 539 patients were included (median age, 78 years). The patients experienced a low overall treatment burden (median, 8.6) and good cosmetic results. The predictors of higher treatment burden were instrumental activities of daily living (iADL) dependency, female sex, complications, larger tumor diameter, and polypharmacy. Thirty-five patients (6.5%) died (none of the deaths were due to BCC) within the follow-up period; the predictors of mortality were increasing comorbidity index and iADL dependency. No difference in these outcomes was seen between Mohs micrographic surgery and conventional excision after correction for covariates. Age was not significantly associated with any outcome. LIMITATIONS: A selection bias may exist owing to the observational design. CONCLUSION: BCC management decisions based on chronological age alone should be avoided, whereas more attention is recommended for patient-related factors. Based on these data, early BCC intervention is beneficial for robust and fit patients or those experiencing symptoms.

Comparing methotrexate monotherapy with methotrexate plus leflunomide combination therapy in psoriatic arthritis (COMPLETE-PsA): a double-blind, placebo-controlled, randomised, trial.

BACKGROUND: Conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) are the preferred first-line treatment in patients with psoriatic arthritis, although there is a paucity of evidence for the efficacy of conventional synthetic DMARDs and especially their combination. We aimed to investigate whether a combination of methotrexate plus leflunomide is superior to methotrexate monotherapy at improving disease activity in patients with psoriatic arthritis. METHODS: This single centre, investigator-initiated, double-blind, randomised, placebo-controlled trial was conducted at Sint Maartenskliniek in the Netherlands (locations included Boxmeer, Geldrop, Woerden, and Nijmegen). Patients aged 16 years or older with a clinical diagnosis of psoriatic arthritis and active disease (defined as two or more swollen joints; dactylitis counting as one swollen joint) were included. Patients were randomly allocated (1:1) and stratified by high disease activity (psoriatic arthritis disease activity score [PASDAS] ≥5·4) to either methotrexate plus leflunomide (combination therapy) or methotrexate plus placebo (monotherapy), using computer-generated stratified variable block randomisation. In both groups, patients received oral methotrexate 15 mg per week for the first 4 weeks and 25 mg per week thereafter combined with two leflunomide 10 mg tablets once per day or two placebo tablets. During the study period, the patients, nurses, researchers, and treating physicians were all masked to treatment allocation. The primary outcome was the difference in mean PASDAS at week 16, adjusted for baseline PASDAS, between the combination and monotherapy groups, assessed in the intention-to-treat population. This trial was registered with the Netherlands Trial Register (NL7404) on Dec 3, 2018. FINDINGS: Between Feb 19, 2019, and March 11, 2021, 82 patients were screened for eligibility. Four patients were ineligible and 78 were enrolled and randomly assigned to either methotrexate plus leflunomide (n=39) or methotrexate plus placebo (n=39). 50 (64%) of 78 patients were male, 28 (36%) were female, and the median age of patients was 55·0 years (IQR 42·0-64·0). Methotrexate plus leflunomide combination therapy was superior to methotrexate monotherapy at week 16 (PASDAS 3·1 [SD 1·4] vs 3·7 [SD 1·3]; treatment difference -0·6, 90% CI -1·0 to -0·1; p=0·025). There were no study deaths. The most frequently occurring adverse events were nausea or vomiting (17 [44%] of 39 patients in the methotrexate plus leflunomide group vs 11 [28%] of 39 in the methotrexate plus placebo group), tiredness (9 [23%] vs 13 [33%]) and elevated alanine aminotransferase (12 [31%] vs 7 [18%]. Generally, the incidence of mostly mild adverse events was higher in the methotrexate plus leflunomide group than in the methotrexate plus placebo group. INTERPRETATION: Methotrexate plus leflunomide combination therapy results in greater improvement in disease activity according to PASDAS in patients with psoriatic arthritis. However, methotrexate plus leflunomide combination therapy is less well tolerated than methotrexate monotherapy. FUNDING: Regional Junior Researcher Grant from the Sint Maartenskliniek.

Dose reduction of the new generation biologics (IL-17 and IL-23 inhibitors) in psoriasis: study protocol for an international, pragmatic, multicenter, randomized, controlled, non-inferiority study-the BeNeBio study.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease for which biologics are effective treatments. Dose reduction (DR) of the first generation biologics seems a promising way for more efficient use of expensive biologics. A substantial part of patients on tumor necrosis factor (TNF)-alfa inhibitors and ustekinumab could successfully lower their dose, after following a tightly controlled DR strategy. The objective of this study is to assess whether controlled DR of interleukin (IL)-17 and IL-23 inhibitors in psoriasis patients with low disease activity is non-inferior (NI) to usual care (UC). METHODS: This is an international, prospective, multicenter, pragmatic, randomized, non-inferiority trial. A total of 244 patients with stable low disease activity (Psoriasis Area and Severity Index (PASI) ≤ 5) for at least 6 months and using secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, or tildrakizumab in the standard dose, together with stable low disease activity, defined as a PASI ≤ 5 and Dermatology Life Quality Index (DLQI) ≤ 5 at the moment of inclusion, will be randomized 2:1 to DR or UC. In the DR group, dosing intervals will be prolonged stepwise to achieve 66% and 50% of the original dose. Disease activity is monitored every 3 months by PASI and DLQI. In case of disease flare (i.e., PASI and/or DLQI increase), treatment is adjusted to the previous effective dose. The primary outcome is the incidence proportion of persistent flares (PASI > 5 for ≥ 3 months), which will be compared between arms. Secondary outcomes include proportion of patients with successful DR, (course of) PASI and DLQI, serious adverse events (SAEs), health-related quality of life, costs, and pharmacokinetic profile. Outcomes of DR will be compared to UC. DISCUSSION: With this study, we aim to assess whether DR of IL-17 and IL-23 inhibiting biologics can be achieved for psoriasis patients with low disease activity, without losing disease control. Reducing the dose may lead to more efficient use of biologics. TRIAL REGISTRATION: ClinicalTrials.gov NCT04340076 . Registered on April 9 2020.

Blood-Based Immune Profiling Combined with Machine Learning Discriminates Psoriatic Arthritis from Psoriasis Patients.

Psoriasis (Pso) is a chronic inflammatory skin disease, and up to 30% of Pso patients develop psoriatic arthritis (PsA), which can lead to irreversible joint damage. Early detection of PsA in Pso patients is crucial for timely treatment but difficult for dermatologists to implement. We, therefore, aimed to find disease-specific immune profiles, discriminating Pso from PsA patients, possibly facilitating the correct identification of Pso patients in need of referral to a rheumatology clinic. The phenotypes of peripheral blood immune cells of consecutive Pso and PsA patients were analyzed, and disease-specific immune profiles were identified via a machine learning approach. This approach resulted in a random forest classification model capable of distinguishing PsA from Pso (mean AUC = 0.95). Key PsA-classifying cell subsets selected included increased proportions of differentiated CD4+CD196+CD183-CD194+ and CD4+CD196-CD183-CD194+ T-cells and reduced proportions of CD196+ and CD197+ monocytes, memory CD4+ and CD8+ T-cell subsets and CD4+ regulatory T-cells. Within PsA, joint scores showed an association with memory CD8+CD45RA-CD197- effector T-cells and CD197+ monocytes. To conclude, through the integration of in-depth flow cytometry and machine learning, we identified an immune cell profile discriminating PsA from Pso. This immune profile may aid in timely diagnosing PsA in Pso.

Evaluation of Watchful Waiting and Tumor Behavior in Patients With Basal Cell Carcinoma: An Observational Cohort Study of 280 Basal Cell Carcinomas in 89 Patients.

IMPORTANCE: Few studies have examined watchful waiting (WW) in patients with basal cell carcinoma (BCC), although this approach might be suitable in patients who might not live long enough to benefit from treatment. OBJECTIVE: To evaluate reasons for WW and to document the natural course of BCC in patients who chose WW and reasons to initiate later treatment. DESIGN, SETTING, AND PARTICIPANTS: An observational cohort study was performed at a single institution between January 2018 and November 2020 studying patients with 1 or more untreated BCC for 3 months or longer. EXPOSURES: Watchful waiting was chosen by patients and proxies regardless of this study. MAIN OUTCOME AND MEASURES: The reasons for WW and treatment were extracted from patient files and were categorized for analyses. Linear mixed models were used to estimate tumor growth and identify covariates associated with tumor growth. RESULTS: Watchful waiting was chosen for 280 BCCs in 89 patients (47 men [53%] and 42 women [47%]), with a median (interquartile range [IQR]) follow-up of 9 (4-15) months. The median (IQR) age of the included patients was 83 (73-88) years. Patient-related factors or preferences (ie, prioritizations of comorbidities, severe frailty, or limited life expectancy) were reasons to initiate WW in 74 (83%) patients, followed by tumor-related factors (n = 49; 55%). Treatment-related and circumstantial reasons were important for 35% and 46% of the patients, respectively. The minority of tumors increased in size (47%). Tumor growth was associated with BCC subtype (odds ratio, 3.35; 95% CI, 1.47-7.96; P = .005), but not with initial tumor size and location. The estimated tumor diameter increase was 4.46 mm (80% prediction interval, 1.42 to 7.46 mm) in 1 year for BCCs containing at least an infiltrative/micronodular component and 1.06 mm (80% prediction interval, -1.79 to 4.28 mm) for the remaining BCCs (only nodular/superficial component/clinical diagnosis). Most common reasons to initiate treatment were tumor burden or potential tumor burden, resolved reason(s) for WW, and reevaluation of patient-related factors. CONCLUSIONS AND RELEVANCE: In this cohort study of patients with BCC, WW was an appropriate approach in several patients, especially those with asymptomatic nodular or superficial BCCs and a limited life expectancy. Patients should be followed up regularly to determine whether a WW approach is still suitable and whether patients still prefer WW and to reconsider consequences of treatment and refraining from treatment.

Clinical, laboratory, and genetic markers for the development or presence of psoriatic arthritis in psoriasis patients: a systematic review.

Twenty to thirty percent of psoriasis (Pso) patients will develop psoriatic arthritis (PsA). Detection of Pso patients that are (at risk for) developing PsA is essential to prevent structural damage. We conducted a systematic search of five bibliographic databases, up to May 2020. We searched for studies assessing markers (clinical, laboratory, genetic) associated with the development or presence of PsA in Pso patients. Study selection and quality assessment of the included studies was performed, followed by a qualitative best evidence synthesis to determine the level of evidence for a marker and its association with concomitant/developing PsA in Pso. Overall, 259 possible markers were identified in 119 studies that met the inclusion criteria. Laboratory markers related to inflammation and bone metabolism reached a strong level of evidence for the association (not prediction) of PsA in Pso. Only CXCL10 showed strong evidence for a positive predictive value for PsA in Pso. The importance of timely detecting PsA in a Pso population, and finding more (bio)markers contributing to early detection, remains high.

Pregnancy and neonatal outcomes in women with immune mediated inflammatory diseases exposed to anti-tumor necrosis factor-α during pregnancy: A systemic review and meta-analysis.

BACKGROUND: Anti-TNFα is increasingly used as treatment for immune mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and psoriasis (PS). However, the impact of anti-TNFα during pregnancy on mother and newborn is under debate. This requires a sound knowledge of the effects of this treatment on pregnancy and neonatal outcomes. OBJECTIVES: To assess pregnancy and neonatal outcomes after anti-TNFα therapy during pregnancy in women with IMID, specifically IBD, RA and PS. METHODS: We performed a systematic review and meta-analysis of 39 studies assessing pregnancy and neonatal outcomes of women with IMID exposed to anti-TNFα agents during pregnancy. We used a random-effects model to determine pooled outcome measures. RESULTS: An increased risk of preterm births (OR 1.45, 95% CI = 1.16 to 1.82, p = 0.001) and infections in newborns (OR 1.12, 95% CI = 1.00 to 1.27, p = 0.05)) was seen for women in the combined group of IMID exposed to anti-TNFα compared to diseased controls. Specifically for IBD patients exposed to anti-TNFα, the risk was increased for preterm birth (OR 1.66, 95% CI = 1.14 to 2.42, p = 0.009), and low birth weight (OR 1.49, 95% CI = 1.01 to 2.20, p = 0.047) compared to diseased controls. Combined data from studies of women with RA and PS, showed no increased risk for adverse pregnancy outcome after exposure to anti-TNFα. Most children of mothers with IMID received vaccination according to national vaccination schemes and only minor adverse events were reported. CONCLUSION: Exposure to anti-TNFα agents during pregnancy is associated with increased risk of preterm birth and infections in newborns of women with IMID compared to diseased controls. The risk of preterm birth and low birth weight was increased in women with IBD specifically. The increased risk of infections in newborns underlines the importance of vaccination, which seems to be safe in children exposed to anti-TNFα. Delay of vaccination is therefore unnecessary in these children. These data may aid in balancing the continuing anti-TNFα therapy versus the risk of adverse pregnancy outcomes.

Skin Surface Protein Detection by Transdermal Analysis Patches in Pediatric Psoriasis.

INTRODUCTION: Transdermal analysis patches (TAPs) noninvasively measure soluble proteins in the stratum corneum. Ultimately, such local protein profiles could benefit the search for biomarkers to improve personalized treatment in psoriasis. This study aimed to explore the patient friendliness and protein detection by TAP in pediatric psoriasis in daily clinical practice. METHODS: In this observational study, TAPs measuring CXC chemokine ligand (CXCL)-1/2, CC chemokine ligand (CCL)-27, interleukin (IL)-1RA, IL-23, IL-1α, IL-8, IL-4, IL-22, IL-17A, vascular endothelial growth factor (VEGF), human beta-defensin (hBD)-2, hBD-1, and kallikrein-related peptidase (KLK)-5 were applied on lesional, peri-lesional, and non-lesional skin sites of psoriasis patients aged >5 to <18 years. Discomfort during TAP removal as an indicator for patient friendliness was assessed by visual analogue scale (VAS; range 0-10). RESULTS: Thirty-two patients (median age 14.0 years) were included, of which 19 were treated with solely topical agents and 13 with systemic treatment. The median VAS of discomfort during TAP removal was 1.0 (interquartile range 1.0). Significantly higher levels in lesional versus non-lesional skin were found for IL-1RA, VEGF, CXCL-1/2, hBD-2, and IL-8, whereas lower levels were found for IL-1α. Skin surface proteins were measured in both treatment groups, with significant higher lesional levels of KLK-5, IL-1RA, hBD-2, IL-1α, IL-23, and CCL-27 in the systemic treatment group. CONCLUSION: The TAP platform holds the potential for patient-friendly and noninvasive monitoring of skin-derived proteins in pediatric psoriasis patients in daily clinical practice.

Measuring disease activity in psoriatic arthritis: PASDAS implementation in a tightly monitored cohort reveals residual disease burden.

OBJECTIVES: We aimed to investigate the disease activity and overall disease burden of (subgroups of) patients with PsA using the Psoriatic Arthritis Disease Activity Score (PASDAS) in an already tightly monitored cohort. METHODS: This is a cross-sectional study evaluating data from the first visit of 855 PsA patients after implementation of the PASDAS in our tightly monitored cohort [e.g. DAS 28 (DAS28) was provided as an anchor]. Differences in clinical outcomes between subgroups of patients using established cut-offs for disease activity status [i.e. very low (VLDA), low (LDA), moderate (MDA), and high disease activity (HDA)] were examined. RESULTS: Based on the PASDAS, 53.1% of patients were in VLDA/LDA. 29.5% of patients had ≥1 swollen joint, 20.6% had ≥1 enthesitis index point and 3.0% had active dactylitis. Based on DAS28, 77.5% of the patients were in VLDA/LDA. Patients reaching both DAS28 VLDA/LDA status and PASDAS VLDA/LDA status [N = 445 (52.0%)] were compared with patients reaching only DAS28 VLDA/LDA status [N = 218 (25.5%)]. For these latter patients, significantly worse scores on separate parameters were found in measures used for PASDAS/DAS28 calculation (e.g. swollen and tender joint count and patient's visual analogue scale global disease activity) as well as other disease measures (e.g. function and inflammatory back pain). This result remained, even when the stricter VLDA cut-off was used for the DAS28. CONCLUSION: PASDAS implementation uncovered relevant residual disease activity in a quarter of patients previously assessed as being in DAS28 VLDA/LDA, underscoring the potential value of PASDAS measurements in PsA clinical care.

Value of GPSkin for the measurement of skin barrier impairment and for monitoring of rosacea treatment in daily practice.

BACKGROUND: Stratum corneum hydration (SCH) and transepidermal water loss (TEWL) provide useful information about skin barrier function. This study aimed to determine the value of GPSkin Pro, a new handheld device determining both SCH and TEWL, to measure skin barrier impairment and to monitor barrier function in rosacea in daily practice. MATERIALS AND METHODS: Two pilots were performed. Pilot 1: in 27 healthy participants, GPSkin SCH and TEWL were compared to Aquaflux® and Epsilon® values at the forearm before and after skin barrier perturbation via tapestripping. Moreover, GPSkin values were measured at both cheeks without intervention. Pilot 2: in 16 rosacea patients, GPSkin measurements were performed at the forearm, and at both cheeks before and during anti-inflammatory treatment. They were compared to clinical symptoms and to GPSkin values from pilot 1. RESULTS: Pilot 1: after merging data from before and after tapestripping, a strong correlation was observed between GPSkin TEWL and Aquaflux® (Rs  = 0.9256), and GPSkin SCH and Epsilon® (Rs  = 0.8798). Pilot 2: SCH was significantly lower at the cheeks of rosacea patients compared to controls, with a normalizing trend during successful treatment. TEWL was comparable among patients and controls and did not change during treatment at all locations. CONCLUSION: The GPSkin determines TEWL and SCH accurately in healthy and impaired skin barrier state and can monitor skin barrier function in rosacea during treatment. The GPSkin device is much more practical compared to previous skin barrier tools when used in clinical practice. Its further validation in other inflammatory skin diseases is recommended.

Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.

OBJECTIVES: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD. METHODS: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA. RESULTS: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction. CONCLUSION: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.