Evaluation of a One-step Dose Reduction Strategy of Adalimumab, Etanercept and Ustekinumab in Patients with Psoriasis in Daily Practice.

Dose reduction of biologics for psoriasis could contribute to lower drug exposure. This study evaluated a one-step, tightly controlled, biologic dose reduction strategy in a prospective daily practice cohort. In patients with psoriasis with low disease activity using adalimumab, etanercept or ustekinumab for at least 6 months, the dosing interval was prolonged with 33%. Patients could return to their normal dosing interval in case of disease flare. Of 108 eligible patients, 80 started dose reduction and were analysed. In total, 36/80 patients (45.0%) discontinued dose reduction after 19 months (95% confidence interval 14.9-23.1 months). Of 67 patients with 1-year follow-up, 45 (67.2%) still used the lower dose after 1 year. No serious adverse events related to dose reduction occurred. Cumulative dose and costs decreased by 22.7% during 1 year. In conclusion, a one-step tightly controlled dose reduction strategy for adalimumab, etanercept and ustekinumab has considerable potential to safely decrease biologic dosages in patients with psoriasis in daily practice.

Effectiveness and Safety of Systemic Therapy for Psoriasis in Older Adults: A Systematic Review.

Importance: Treating older adults with psoriasis can be challenging owing to comorbidities, concomitant medication use, and consequent safety risks. Although many studies focus on the effectiveness and safety of systemic antipsoriatic therapies in the general population, their effectiveness in older adults with psoriasis has not been systematically assessed. Objective: To evaluate the effectiveness and safety of systemic antipsoriatic therapies in patients 65 years or older. Evidence Review: A systematic literature search was conducted in Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL) on November 11, 2019. No date limit was used. Randomized clinical trials, cohort studies, large case series, and meta-analyses assessing efficacy (or effectiveness) and/or safety of systemic antipsoriatic therapies in patients 65 years or older were included. Findings: The initial search yielded 11 096 results, of which 31 unique articles with 39 561 patients were included in analysis. Overall, limited data were available per systemic agent, and overall quality of the included studies on conventional systemic therapies was low. At the end of the induction phase (12-16 weeks after start of treatment), a reduction of 75% in Psoriasis Area and Severity Index was achieved in 49% of 74 methotrexate sodium users 65 years or older, 46% to 52.6% of 178 older cyclosporin users, 27% to 47.8% of 108 older acitretin users, 15.6% to 64% of 256 etanercept users 65 years or older, 66.7% to 93% of 43 infliximab users 65 years or older, 60.7% to 65% of 100 adalimumab users 65 years or older, 56.5% of 46 ustekinumab users 65 years or older, and 86.4% of 67 secukinumab users 65 years or older. Effectiveness of acitretin, etanercept, adalimumab, and secukinumab appeared not to be associated with age; studies regarding other systemic antipsoriatic therapies did not provide age group comparisons. Older age was significantly associated with renal function deterioration in cyclosporin users and with lymphopenia in fumaric acid esters users (hazard ratio, 2.42; 95% CI, 1.65-3.55; P < .001). Infections were the most frequently reported adverse event in patients 65 years or older using biologics, but no significant association with age was found. Conclusions and Relevance: On the basis of limited available evidence, age alone should not be a limiting factor in psoriasis management. Awareness of comorbidities and concomitant medication use is very important, as well as appropriate dosing and frequent laboratory and clinical monitoring. More real-world evidence and (sub)analyses of prospective cohort studies on the effectiveness and safety of systemic therapies in older adults are critical to optimize personalized, effective, and safe antipsoriatic management in this growing patient group.

Comparison of Tightly Controlled Dose Reduction of Biologics With Usual Care for Patients With Psoriasis: A Randomized Clinical Trial.

Importance: Biologics revolutionized the treatment of psoriasis. Biologics are given in a fixed dose, but lower doses might be possible. Objective: To investigate whether dose reduction (DR) of biologics in patients with stable psoriasis is noninferior to usual care (UC). Design, Setting, and Participants: This pragmatic, open-label, prospective, controlled, noninferiority randomized clinical trial was conducted from March 1, 2016, to July 22, 2018, at 6 dermatology departments in the Netherlands. A total of 120 patients with plaque psoriasis and stable low disease activity who were receiving treatment with adalimumab, etanercept, or ustekinumab were studied. Interventions: Patients were randomized 1:1 to DR (n = 60) or UC (n = 60). In the DR group, injection intervals were prolonged stepwise, leading to 67% and 50% of the original dose. Main Outcomes and Measures: The primary outcome was between-group difference in disease activity corrected for baseline at 12 months compared with the predefined noninferiority margin of 0.5. Secondary outcomes were Psoriasis Area and Severity Index (PASI) score and health-related quality of life (including Dermatology Life Quality Index [DLQI] and Medical Outcomes Study 36-Item Short Form Health Survey scores), proportion of patients with short and persistent flares (defined as PASI and/or DLQI scores >5 for ≥3 months), and proportion of patients with successful dose tapering. Results: Of 120 patients (mean [SD] age, 54.0 [13.2] years; 82 [68%] male), 2 patients were lost to follow-up, 2 patients had a protocol violation, and 5 patients had a protocol deviation, leaving 111 patients for the per-protocol analysis (53 in the DR group and 58 in the UC group). The median PASI scores at month 12 were 3.4 (interquartile range [IQR], 2.2-4.5) in the DR group and 2.1 (IQR, 0.6-3.6) in the UC group (mean difference, 1.2; 95% CI, 0.7-1.8). This indicates that noninferiority was not demonstrated for DR compared to UC. The median DLQI score at month 12 was 1.0 (IQR, 0.0-2.0) in the DR group and 0.0 (IQR, 0.0-2.0) in the UC group (mean difference, 0.8; 95% CI, 0.3-1.3), indicating noninferiority for DR compared with UC. No significant difference was found regarding persistent flares between groups (n = 5 in both groups). Twenty-eight patients (53%; 95% CI, 39%-67%) in the DR group tapered their dose successfully at 12 months. No severe adverse events related to the intervention occurred. Conclusions and Relevance: In this trial, noninferiority was not demonstrated for DR of adalimumab, etanercept, and ustekinumab based on the PASI in patients with psoriasis compared with UC with the chosen noninferiority margin. However, the strategy was noninferior based on the DLQI. Dose tapering did not lead to persistent flares or safety issues. Trial Registration: ClinicalTrials.gov Identifier: NCT02602925.

Association of HLA-C*06:02 Status With Differential Response to Ustekinumab in Patients With Psoriasis: A Systematic Review and Meta-analysis.

Importance: Previous research showed a differential response to ustekinumab therapy based on HLA-C*06:02 status in patients with psoriasis but consisted mostly of small (and sometimes inconclusive) cohort studies. Objective: To assess whether HLA-C*06:02 status is associated with a differential response to ustekinumab therapy in patients with psoriasis through a systematic review and a meta-analysis of available data. Data Sources: A comprehensive search was conducted using MEDLINE, Embase, the Cochrane Library, Web of Science, and gray literature sources. Databases were searched from January 1, 2000, to May 14, 2018. Search strategies included terms and synonyms for psoriasis, HLA-C, and ustekinumab. Languages were restricted to English, French, German, and Dutch. Study Selection: Studies were included if they reported the association between HLA-C*06:02 status and 75% improvement in Psoriasis Area and Severity Index (PASI75) response to ustekinumab therapy in patients with plaque psoriasis after 6 and/or 3 months of treatment. Randomized clinical trials and observational studies were included. Screening and selection were performed independently by 2 reviewers. Data Extraction and Synthesis: HLA-C*06:02 genotype status and PASI75 response rates were extracted by 2 reviewers. Data were pooled using random-effects models. Heterogeneity was assessed using the τ2 and I2 statistic. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines were followed. Main Outcome and Measure: The primary outcome was the risk difference of achieving PASI75 after 6 months of ustekinumab therapy between HLA-C*06:02-positive and HLA-C*06:02-negative patients. Results: A total of 8 studies were reviewed; 1048 patients were included for meta-analyses, and 937 patients were included for the primary analysis of PASI75 response after 6 months of treatment. Random-effects meta-analysis showed a risk difference of 0.24 (95% CI, 0.14-0.35; P < .001) in favor of HLA-C*06:02-positive patients. The median PASI75 response rate in the HLA-C*06:02-positive group was 92% (pooled, 89%; range, 62%-98%). For HLA-C*06:02-negative patients, the median response rate was 67% (pooled, 62%; range, 40%-84%). Substantial heterogeneity may have been present, with an I2 of 82%. Conclusions and Relevance: The meta-analysis showed a differential response to ustekinumab therapy based on HLA-C*06:02 status in patients with psoriasis. Although HLA-C*06:02-positive patients had high PASI75 response rates after 6 months, the PASI75 response rate was also high in the HLA-C*06:02-negative group. There appears to be no rationale for excluding patients from ustekinumab treatment based on a negative HLA-C*06:02 status.

Initial Results of Secukinumab Drug Survival in Patients with Psoriasis: A Multicentre Daily Practice Cohort Study.

Interleukin 17-antagonist secukinumab demonstrated high efficacy for treatment of psoriasis in randomized controlled trials. However, performance in daily practice may differ from trials. Drug survival is a comprehensive outcome covering effectiveness and safety, suitable for analyses of daily practice. The aim of this study was to evaluate drug survival of secukinumab in a daily practice psoriasis cohort. Data were collected from 13 hospitals. Drug survival was analysed using Kaplan-Meier survival curves, split for reason of discontinuation. In total, 196 patients were included (83% biologic experienced). Overall, 12 and 18 months drug survival of secukinumab was 76% and 67%, respectively, and was mostly determined by ineffectiveness. There was a trend towards shorter drug survival in women and in biologic experienced patients. Thirteen percent of patients experienced at least one episode of fungal infection. This is one of the first studies of drug survival of secukinumab in patients with psoriasis treated in daily practice.

Tight controlled dose reduction of biologics in psoriasis patients with low disease activity: a randomized pragmatic non-inferiority trial.

BACKGROUND: Psoriasis is an immune-mediated chronic inflammatory skin disorder for which several targeted biologic therapies became available in the last 10 years. Data from patients with rheumatoid arthritis revealed that dose tapering combined with tight control of disease activity is successful. For psoriasis patients the lowest effective dose of biologics needs to be determined. The objective was to assess whether dose tapering of biologics guided by Psoriasis Area and Severity Index (PASI) and Dermatology Quality of Life Index (DLQI) scores in psoriasis patients with controlled disease activity is non-inferior (NI) to usual care. METHODS/DESIGN: This is a multicenter, pragmatic, randomized, non-inferiority trial with cost- effectiveness analysis. One hundred and twenty patients with stable low disease activity (PASI ≤ 5 and DLQI ≤ 5) for at least 6 months with a stable use of adalimumab, etanercept or ustekinumab will be randomized 1:1 to the dose reduction group or usual care. In the dose reduction group, the treatment intervals will be prolonged stepwise, resulting in a 33% and 50% dose reduction, respectively. Disease activity is monitored every three months with PASI and DLQI. In case of flare the treatment is adjusted to the previous effective dose. The primary outcome (PASI) at 12 months will be analyzed with ANCOVA in which the baseline PASI will be included as covariate to gain efficiency. The secondary outcomes include number of and time to disease flares, health-related quality of life, serious adverse events, and costs. DISCUSSION: With this study we want to assess whether disease activity guided dose reduction of biologics can be achieved for psoriasis patients with low stable disease activity, without losing disease control. By using the lowest effective dose of biologics, we expect to minimize side effects and save costs. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov ( NCT 02602925 ). Trial registration date October 9 2015.

The utility of GLUT1 as a diagnostic marker in cutaneous vascular anomalies: A review of literature and recommendations for daily practice.

OBJECTIVE: To assess the utility of GLUT1 as an immunohistochemical marker in the diagnostics of cutaneous vascular anomalies. METHODS: A systematic literature search was conducted for studies on GLUT1 staining patterns in cutaneous vascular lesions. Data was grouped according to the latest ISSVA classification for vascular anomalies. RESULTS: Vascular tumors: GLUT1 staining was positive in 368/386 (95%) of infantile hemangiomas. Congenital hemangiomas (16 cases) and kaposiform hemangioendotheliomas (62 cases) were all negative for GLUT1. Angiosarcomas were GLUT1 positive in 12/39 (31%) and epithelioid hemangioendotheliomas in 2/27 (7%) of cases. Vascular malformations: All vascular malformations (33 arteriovenous malformations, 16 capillary malformations, 64 lymphatic malformations, 54 venous malformations, 3 venous-lymphatic malformations and 3 capillary venous-lymphatic malformations) were negative for GLUT1 staining. Unclassified vascular anomalies: Angiokeratomas were GLUT1 positive in 1/15 (7%) and verrucous hemangiomas in 71/100 (71%) of cases. Microvenular hemangiomas were negative for GLUT1 in all 9 cases. CONCLUSIONS: GLUT1 can be used as an additional diagnostic tool in cutaneous vascular lesions. A negative GLUT1 stain renders a diagnosis of infantile hemangioma unlikely. A positive GLUT1 stain excludes vascular malformations and is suggestive of infantile hemangioma. One must be cautious, however, that the final diagnosis is made through interpretation of all clinical and diagnostic features, and not based on GLUT1 staining alone.

The Epidemiology and Clinicopathological Features of Basal Cell Carcinoma in Patients 80 Years and Older: A Systematic Review.

Importance: The number of very elderly (≥80 years) is rapidly growing worldwide. Basal cell carcinoma (BCC) are common in this age group and treatment is often challenging in this population. Objective: Obtaining an overview of the epidemiology and clinicopathological features of BCC in the very elderly to guide clinicians and policy makers. Evidence Review: A systematic review of literature was performed using PubMed, Excerpta Medica Database (EMBASE), and the Cochrane Library. Study selection, quality assessment, and data extraction was performed by 2 independent reviewers. For quality assessment (including the risk of bias) the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist was used, combined with the Quality Rating Scheme for Studies and Other Evidence. Data were described though a narrative synthesis and tabulation. Findings: Of 13 628 studies identified, 83 studies were included and quality assesment was performed for 76 studies; 27 studies (representing >350 000 patients) were found that included age-specific incidence rates of BCC in the very elderly. High and increasing incidence rates of BCC in the very elderly were found ranging from 13 to 12 112 per 100 000 person-years, strongly depending on factors like study population and clinical setting. Basal cell carcinoma in the very elderly were more common in men, mostly of the nodular subtype, and located in the head and neck region. Interpretation and generalization of the data was limited by the heterogeneity of study populations, methods, and outcomes. Data concerning impact on health-related quality of life (HRQoL) and prognostication were scarce. Conclusions and Relevance: The incidence of BCC among the very elderly is high and increasing. Epidemiologic and clinicopathological data from current literature provide only limited guidance in clinical decision making owing to heterogeneity and scarcity. Future research should focus more specifically on BCC in the very elderly, together with prognostication and their relation with HRQoL in both the short and longer term.