Kayleigh Mason

Risk of cancer in patients with psoriasis on biological therapies: a systematic review

Biological therapies are highly effective in psoriasis, but have profound effects on innate and adaptive immune pathways that may negatively impact on cancer immunosurveillance mechanisms.

Identification of factors that may influence the selection of first-line biological therapy for people with psoriasis: a prospective, multicentre cohort study

The Psoriasis Stratification to Optimise Relevant Therapy (PSORT) consortium has a collective aim to develop a prescribing algorithm to help stratify eligible patients with psoriasis to the most appropriate biological treatment. To facilitate the adoption of a stratified approach, it is necessary to first understand the factors driving the choice of first‐line biological therapy.

Differential Drug Survival of Second-Line Biologic Therapies in Patients with Psoriasis: Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

Little is known about the drug survival of second-line biologic therapies for psoriasis in routine clinical practice. We assessed drug survival of second-line biologic therapies and estimated the risk of recurrent discontinuation due to adverse events or ineffectiveness in patients with psoriasis who had failed a first biologic therapy and switched to a second in a large, multicenter pharmacovigilance registry (n = 1,239; adalimumab, n = 538; etanercept, n = 104; ustekinumab, n = 597). The overall drug survival rate in the first year after switching was 77% (95% confidence interval = 74–79%), falling to 58% (55–61%) in the third year. Female sex, multiple comorbidities, concomitant therapy with cyclosporine, and a high Psoriasis Area and Severity Index at switching to the second-line biologic therapy were predictors of overall discontinuation (multivariable Cox proportional hazard model). Compared to adalimumab, patients receiving etanercept were more likely to discontinue therapy (hazard ratio = 1.87, 95% confidence interval = 1.24–2.83), whereas patients receiving ustekinumab were more likely to persist (hazard ratio = 0.46; 95% confidence interval = 0.33–0.64). Discontinuation of the first biologic therapy because of adverse events was associated with an increased rate of second drug discontinuation because of adverse events (hazard ratio = 2.55; 95% confidence interval = 1.50–4.32). In conclusion, drug survival rates differed among biologic therapies and decreased over time; second-line discontinuation because of adverse events was more common among those who discontinued first-line treatment for this reason. The results of this study should support clinical decision making when choosing second-line biologic therapy for patients with psoriasis.

Comparison of Drug Discontinuation, Effectiveness, and Safety Between Clinical Trial Eligible and Ineligible Patients in BADBIR

Importance Patients with psoriasis enrolled in clinical trials of biologics may not be representative of the real-world population. There is evidence that patients ineligible for such trials have a greater risk of serious adverse events (SAEs), but the effect on drug discontinuation and effectiveness are unknown. Objective To determine whether (1) drug discontinuation, (2) effectiveness, and (3) rates of SAEs differ in patients with psoriasis categorized as eligible or ineligible for clinical trials. Design, Setting, and Participants An observational study using 157 dermatology centers in the United Kingdom and Republic of Ireland was carried out wherein we applied the eligibility criteria of clinical trials of biologic therapies for psoriasis to patients who were being followed up in the British Association of Dermatologists Biologic Interventions Register (BADBIR) and being prescribed biologics as part of standard clinical care. Patients with psoriasis registered to BADBIR who were taking etanercept (enbrel only; n = 1509), adalimumab (n = 4000), and ustekinumab (n = 1627) with at least 1 follow-up visit. Eligibility criteria were extracted from phase 3 licensing trials for etanercept, adalimumab, and ustekinumab for the treatment of moderate to severe psoriasis. Patients in BADBIR with a missing baseline Psoriasis Area and Severity Index (PASI) or baseline PASI value less than 10 (etanercept) or less than 12 (adalimumab; ustekinumab) but who would otherwise be eligible were investigated separately. Eligibility categories applied to BADBIR included: eligible, ineligible, insufficient baseline PASI only, and missing baseline PASI only. Main Outcomes and Measures (1) Drug discontinuation: cumulative incidence at 12 months by stop reason per eligibility category and drug; (2) effectiveness: linear regression of absolute change in PASI from baseline to 6 and 12 months; and (3) SAEs: incidence rate ratio (IRR) at 12 months between eligibility categories per drug. Results The mean (SD) age of the 7136 patients included in the analysis was 45 (13) years and 2924 (41%) were women and 4212 (59%) were men. Of 7136 patients, 839 (56%) etanercept, 2219 (56%) adalimumab, and 754 (46%) ustekinumab registrations were categorized as eligible. The most common reasons for ineligibility were diabetes (etanercept, 143 [9%]; ustekinumab, 201 [12%]) and nonchronic plaque psoriasis (adalimumab, 157 [4%]). Patients categorized as ineligible (etanercept, 367 [24%]; adalimumab, 282 [7%]; ustekinumab, 394 [24%]) achieved a smaller absolute change in PASI after 6 and 12 months (adalimumab, ustekinumab), and had significantly higher rates of SAEs compared with the eligible category (etanercept: IRR, 1.9; 95% CI, 1.4-2.6; adalimumab: IRR, 2.0; 95% CI, 1.5-2.6; ustekinumab: IRR, 2.8; 95% CI, 2.1-3.8). No significant differences in drug discontinuation were observed between categories. Conclusions and Relevance Clinical trial effectiveness and safety outcomes are not representative of real-world patients in BADBIR patients categorized as ineligible for such trials.

Intentional and unintentional medication non-adherence in psoriasis: the role of patients’ medication beliefs and habit strength

Medication non-adherence is a missed opportunity for therapeutic benefit. We assessed “real-world” levels of self-reported non-adherence to conventional and biologic systemic therapies used for psoriasis and evaluated psychological and biomedical factors associated with non-adherence using multivariable analyses. Latent profile analysis was used to investigate whether patients can be categorized into groups with similar medication beliefs. Latent profile analysis categorizes individuals with similar profiles on a set of continuous variables into discrete groups represented by a categorical latent variable. Eight hundred and eleven patients enrolled in the British Association of Dermatologists Biologic Interventions Register were included. Six hundred and seventeen patients were using a self-administered systemic therapy; 22.4% were classified as “non-adherent” (12% intentionally and 10.9% unintentionally). Patients using an oral conventional systemic agent were more likely to be non-adherent compared to those using etanercept or adalimumab (29.2% vs. 16.4%; P ≤ 0.001). Latent profile analysis supported a three-group model; all groups held strong beliefs about their need for systemic therapy but differed in levels of medication concerns. Group 1 (26.4% of the sample) reported the strongest concerns, followed by Group 2 (61%), with Group 3 (12.6%) reporting the weakest concerns. Group 1 membership was associated with intentional non-adherence (odds ratio = 2.27, 95% confidence interval = 1.16−4.47) and weaker medication-taking routine or habit strength was associated with unintentional non-adherence (odds ratio = 0.92, 95% confidence interval = 0.89−0.96). Medication beliefs and habit strength are modifiable targets for strategies to improve adherence in psoriasis.

Psychosocial factors partially mediate the relationship between mechanical hyperalgesia and self-reported pain

Abstract Background and aims: Amplification of sensory signalling within the nervous system along with psychosocial factors contributes to the variation and severity of knee pain. Quantitative sensory testing (QST) is a non-invasive test battery that assesses sensory perception of thermal, pressure, mechanical and vibration stimuli used in the assessment of pain. Psychosocial factors also have an important role in explaining the occurrence of pain. The aim was to determine whether QST measures were associated with self-reported pain, and whether those associations were mediated by psychosocial factors. Methods: Participants with knee pain identified from a population-based cohort completed a tender point count and a reduced QST battery of thermal, mechanical and pressure pain thresholds, temporal summation, mechanical pain sensitivity (MPS), dynamic mechanical allodynia (DMA) and vibration detection threshold performed following the protocol by the German Research Network on Neuropathic Pain. QST assessments were performed at the most painful knee and opposite forearm (if pain-free). Participants were asked to score for their global and knee pain intensities within the past month (range 0–10), and complete questionnaire items investigating anxiety, depression, illness perceptions, pain catastrophising, and physical functioning. QST measures (independent variable) significantly correlated (Spearman’s rho) with self-reported pain intensity (dependent variable) were included in structural equation models with psychosocial factors (latent mediators). Results: Seventy-two participants were recruited with 61 participants (36 women; median age 64 years) with complete data included in subsequent analyses. Tender point count was significantly correlated with global pain intensity. DMA at the knee and MPS at the most painful knee and opposite pain-free forearm were significantly correlated with both global pain and knee pain intensities. Psychosocial factors including pain catastrophising sub-scales (rumination and helplessness) and illness perceptions (consequences and concern) were significant partial mediators of the association with global pain intensity when loaded on to a latent mediator for: tender point count [75% total effect; 95% confidence interval (CI) 22%, 100%]; MPS at the knee (49%; 12%, 86%); and DMA at the knee (63%; 5%, 100%). Latent psychosocial factors were also significant partial mediators of the association between pain intensity at the tested knee with MPS at the knee (30%; 2%, 58%), but not for DMA at the knee. Conclusions: Measures of mechanical hyperalgesia at the most painful knee and pain-free opposite forearm were associated with increased knee and global pain indicative of altered central processing. Psychosocial factors were significant partial mediators, highlighting the importance of the central integration of emotional processing in pain perception. Implications: Associations between mechanical hyperalgesia at the forearm and knee, psychosocial factors and increased levels of clinical global and knee pain intensity provide evidence of altered central processing as a key mechanism in knee pain, with psychological factors playing a key role in the expression of clinical pain.

Biological therapy for psoriasis and risk of cancer

Psoriasis is a common skin disease that affects up to 3% of people worldwide. Psoriasis is driven by faults in the immune system (which protects the body from infection), which leads to excess skin production. People with the most severe form of psoriasis are given therapies to dampen down the immune system. Systemic therapies (methotrexate and ciclosporin) work to reduce the whole immune system, while biologic therapies (adalimumab, etanercept, and ustekinumab) are targeted to specific immune pathways in the skin. However, there is concern that these therapies may increase the risk of cancer. This study of psoriasis patients in Ireland, Israel, Italy, Spain, and the U.K. aimed to find out if the amount of time spent on these therapies increases the risk of cancer. Each person who developed a cancer during the study was compared to four cancer‐free psoriasis patients (controls) of the same sex, age, dermatology centre, and year of entry into the study. The total time spent on systemic and biologic therapies was calculated for each patient. The authors did not find a difference in the time spent on systemic or biologic therapies between patients who developed a cancer and controls. This result remained unchanged after considering the possible effects of previous exposure to other systemic therapies, duration of psoriasis, smoking, previous exposure to phototherapy and other simultaneous diseases. This study showed that cancers were not more likely to develop after up to 8 years of treatment with biologic therapies.

Identifying demographic, social and clinical predictors of biologic therapy effectiveness in psoriasis: a multicentre longitudinal cohort study

Biologic therapies have revolutionized the treatment of moderate‐to‐severe psoriasis. However, for reasons largely unknown, many patients do not respond or lose response to these drugs.

Completeness of Reporting of Basal Cell Carcinoma and Squamous Cell Carcinoma to a Pharmacovigilance Register and the Health and Social Care Information Centre

Background: Type 2 diabetes mellitus (T2DM) has been suggested as a risk factor for liver, pancreatic, and colorectal cancer. T2DM patients show higher incidences of these cancers compared to the non-diabetic (non-DM) population. Current evidence, however, is inconsistent with respect to the incidences of other gastrointestinal (GI) malignancies. Objectives: To determine incidence rates (IRs) of all GI cancers in patients with and without T2DM. Methods: A retrospective cohort study was conducted using the UK Clinical Practice Research Datalink (CPRD) during 1988-2012. A T2DM cohort of antidiabetic drug users was matched to a non-DM reference cohort, by age, sex, and practice. Crude incidence rates (IRs) per 100,000 person-years (105 py) and 95% confidence intervals (CI) were calculated, stratified by age, sex, and calendar period. IRs were compared using the normal theory test. Results: 333,438 T2DM subjects and 333,438 non- DM subjects were analyzed, with a total duration of follow-up of >3.6 million py and 10,977 observed GI cancer cases. Overall, IRs of any GI cancer (IR 330 vs. 276 per 105 py), liver cancer (IR 26 vs. 8.9 per 105 py), pancreatic cancer (IR 65 vs. 31 per 105 py), and colon cancer (IR 119 vs. 109 per 105 py) were significantly higher in the T2DM cohort compared to the non-DM cohort, whereas the IR of esophageal cancer was significantly lower (IR 41 vs. 47 per 105 py, pBackground: Progressive multifocal leukencephalopathy (PML) is a rare, often fatal viral disease, which affects the white matter of the brain. It is caused by John Cunningham (JC) polyomavirus, whi ...The article investigates the special features of state control over international transfer of special-purpose and dual-use goods. It was established what international organizations was created in the international community to determine the principles of control over international transfer of special-purpose and dual-use goods, as well as the question of Ukraines joining the circle of member-states of such organizations. The structure of the system of export control bodies in Ukraine was defined, as well as the main powers of the State Service of Export Control of Ukraine in the sphere of control over international transfer of goods. The essence and the concept of goods over which international transfer state export control is carried out in accordance with the Ukrainian legislation were revealed, as well as special aspects of the procedure of state control over their international transfer.Background: Different antiplatelet regimens are used for secondary prevention after ischemic stroke (IS)/transient ischemic attack (TIA), but studies on the relative effectiveness and safety of each regimen in daily practice are lacking. Objectives: To assess the relative effectiveness and safety of several antiplatelet regimens as secondary prevention in patients after an IS/TIA in clinical practice. Methods: A cohort study was conducted using the Clinical Practice Research Datalink. Patients aged ≥ 18 years with a first diagnosis of IS/TIA in 1998- 2013 were identified. Antiplatelet exposure was categorized into aspirin-dipyridamole, aspirin-only, clopidogrel-only, aspirin-clopidogrel, other regimens, and no-antiplatelet exposure. The primary effectiveness outcome was a composite endpoint of nonfatal IS, nonfatal myocardial infarction (MI), or cardiovascular (CV) death; and the safety outcome was major bleeding. Time-dependent Cox regression analysis was used to assess the association between antiplatelet regimens and CV effectiveness and major bleeding outcomes. Results: We followed 20,552 IS/TIA patients for a median duration of 2.3 years. There were 5,714 composite events during follow-up. All regimens were effective in reducing the primary effectiveness outcome compared to no-antiplatelet exposure. Aspirin-only, clopidogrel-only, aspirin-clopidogrel and other regimens were significantly (p <0.05) less effective compared to aspirin-dipyridamole (HR: 1.35, 1.12, 1.40, and 1.27, respectively), adjusted for age, sex, lifestyle factors, disease history and CV comedications. All other regimens were also significantly (p <0.05) associated with a higher relative risk of major bleeding compared to aspirin-dipyridamole (HR: 1.21, 1.32, 1.78, and 1.37, respectively), adjusted for age, sex, alcohol use, liver and renal disease, major bleeding history and comedications. Conclusions: Compared to aspirin-dipyridamole, all other antiplatelet regimens are less effective in reducing the risk of nonfatal IS, nonfatal MI or CV death, and associated with a higher risk of major bleeding in patients with IS/TIA.Characteristics of Patients at Initiation of Treatment for Primary Chronic Immune ThrombocytopeniaBackground: Guidelines for cardiovascular secondary prevention are based on evidence from relatively old clinical trials and need to be evaluated in daily clinical practice. Objectives: To evaluate effectiveness of the recommended drug classes after an acute coronary syndrome (ACS) for secondary prevention of cardiovascular diseases and all-cause mortality. Methods: This cohort study used data from a representative sample of the French national healthcare insurance system database (EGB). Patients hospitalised for an incident ACS between 2006 and 2011, and aged ≥ 20 years at time of ACS were included in the study. Patients non-exposed to any of the four recommended drug classes (beta-blockers, antiplatelet agents, statins, and angiotensin-converting-enzyme inhibitors, ACEI, or angiotensin II receptor blockers, ARB) in the first 3 months following ACS or who died during this period were not included in the cohort. Exposure status was determined daily during follow-up. Effectiveness of the four therapeutic classes in preventing the composite outcome ACS, transient ischemic attack, ischemic stroke, or all-cause-death was estimated using a time-dependent Cox proportional hazards model, which was adjusted for time-fixed confounders measured at baseline (general characteristics and characteristics of the initial ACS) and time-dependent confounders during follow-up (co-morbidities and co-medications). Results: Of the 2874 patients included in the study, 33.9% were women and the median age was 67 years (interquartile range, IQR: 56-77). The median time of follow-up was 3.6 years (IQR: 2.2-5.3). The risk of the composite outcome decreased with use of antiplatelet agents (adjusted hazard ratio (aHR) 0.76, 95% confidence interval (CI) 0.63; 0.91), use of statins (aHR 0.71, 95%CI 0.57; 0.87), and use of ACEI/ARB (aHR 0.67, 95%CI 0.57; 0.80). Use of beta-blockers was not associated with a lower risk of the composite outcome (aHR, 0.90, 95%CI 0.74; 1.09]). Conclusions: Use of antiplatelet agents, statins, and ACEI/ARB after an ACS, but not beta-blockers, was associated with a lower risk of cardiovascular morbidity and all-cause mortality.Abstracts of the 32nd International Conference on Pharmacoepidemiology & Therapeutic Risk Management, The Convention Centre Dublin, Dublin, Ireland August 25–28, 2016Background: Cough and angioedema are adverse events associated with especially angiotensinconverting enzyme (ACE) inhibitors but also reported with angiotensin receptor blockers (ARBs) and aliskiren, a direct renin inhibitor (DRI). Susceptibility of developing cough/angioedema with ACE inhibitors depends on ethnicity, which is not documented in spontaneous reporting systems of drug safety. Objectives: To assess the impact of ethnicity on the occurrence of cough/angioedema with renin angiotensin system (RAS) inhibitors using information reported to the the World Health Organization database (VigiBase). Methods: A case/non-case study was performed in VigiBase. Cases were defined as reports of cough/angioedema and non-cases were all reports of other adverse events. The reporting countries were divided into three categories: black African countries, East Asian countries and other countries. Logistic regression analysis was used to assess the association between reporting of cough/angioedema with each class of RAS inhibitors stratified by country group and to control for confounding. Results: The reporting of cough with ACE inhibitors was significantly higher in East Asian countries than black African countries and other countries (adjusted reporting odds ratios (RORs): 256, 95%CI (236-278), 48.9, 95%CI (42.7-56.1) and 35.4, 95%CI (34.8- 35.9), respectively. The reporting of angioedema with ACE inhibitors was significantly higher in black African countries than East Asian countries and other countries (adjusted RORs: 55.3, 95%CI (45.5-67.2), 5.29, 95%CI(3.89-7.21) and 16.5, 95%CI (16.1- 16.8), respectively. There was no difference in reporting of cough/angioedema with ARBs and DRI between black African countries, East Asian countries and other countries. Conclusions: Our results by grouping countries according to ethnicity in VigiBase are consistent with previous results in the literature suggesting that the occurrence of cough with ACE inhibitors is higher in East Asian patients and the occurrence of angioedema with ACE inhibitors is higher in black patients. These findings indicate that ethnicity should be included as scientific parameter in pharmacovigilance.An Automatized Model for Sequential Monitoring of Effectiveness of New Drugs using Dronedarone as ExampleGeneral Pharmacological Treatments Preceding A Primary Chronic Immune Thrombocytopenia DiagnosisBackground: Several studies showed a bidirectional association between type 2 diabetes and psychiatric disorders in adults. There is limited information available about the association of type 1 diabetes (T1D) and psychiatric disorders in children and adolescents. Objectives: To assess the extent of psychiatric medication use before and after the onset of T1D in children and adolescents compared with a reference cohort without T1D. Methods: A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System. All children and adolescents <19 years) with at least two insulin dispensings between 1999 and 2009 were identified as a T1D cohort (N=925) and matched with an up to four times larger diabetes-free reference cohort (N=3591) by age and sex. The period prevalences of psychiatric medication use (psycholeptics (ATC N05) and psychoanaleptics (ATC N06)) were calculated by dividing the number of patients with at least one dispensing by the number of patients available in the cohort during that time. Prevalences were calculated from 5 years before until 5 years after the onset of T1D (the index date in both cohorts) and stratified by age, sex, medication subgroup, and before/after the onset of T1D. Results: The mean age of the study participants was 10.1 years and 51% were boys. The 5-year prevalence of psychiatric medication use before the index date was significantly higher in the T1D cohort than in the reference cohort (7.2 vs. 4.7%, respectively, p=0.002). The same pattern was observed for the period after developing T1D (10.4 vs. 7.9% in the T1D and reference cohort respectively, p=0.015). In both cohorts adolescents (15-19 years) and boys had higher prevalences of psychiatric medication use. This increased prevalence of psychiatric medication use both before and after the index date in T1D cohort was mainly driven by an increased use of psycholeptics (mainly anxiolytics). Conclusions: Children with T1D were more likely to use psychiatric medication in the years before and after the onset of type 1 diabetes. This increased use was mainly driven by psycholeptics both before and after onset of T1D.