British Association Of Dermatologists Biologic Interventions Register Research Articles

Improving the Accuracy of Biologic Drug Survival Data: The Increasing Prevalence of Off-Label Dosing Must Be Considered when Reporting Drug Effectiveness and Safety

Improving the Accuracy of Biologic Drug Survival Data: The Increasing Prevalence of Off-Label Dosing Must Be Considered when Reporting Drug Effectiveness and Safety

Development and validation of a multivariable risk prediction model for serious infection in patients with psoriasis receiving systemic therapy.

SummaryBackgroundPatients with psoriasis are often concerned about the risk of serious infection associated with systemic psoriasis treatments.ObjectivesTo develop and externally validate a prediction model for serious infection in patients with psoriasis within 1 year of starting systemic therapies.MethodsThe risk prediction model was developed using the British Association of Dermatologists Biologic Interventions Register (BADBIR), and the German Psoriasis Registry PsoBest was used as the validation dataset. Model discrimination and calibration were assessed internally and externally using the C‐statistic, the calibration slope and the calibration in the large.ResultsOverall 175 (1·7%) out of 10 033 participants from BADBIR and 41 (1·7%) out of 2423 participants from PsoBest developed a serious infection within 1 year of therapy initiation. Selected predictors in a multiple logistic regression model included nine baseline covariates, and starting infliximab was the strongest predictor. Evaluation of model performance showed a bootstrap optimism‐corrected C‐statistic of 0·64 [95% confidence interval (CI) 0·60–0·69], calibration in the large of 0·02 (95% CI −0·14 to 0·17) and a calibration slope of 0·88 (95% CI 0·70–1·07), while external validation performance was poor, with C‐statistic 0·52 (95% CI 0·42–0·62), calibration in the large 0·06 (95% CI −0·25 to 0·37) and calibration slope 0·36 (95% CI −0·24 to 0·97).ConclusionsWe present the first results of the development of a multivariable prediction model. This model may help patients and dermatologists in the U.K. and the Republic of Ireland to identify modifiable risk factors and inform therapy choice in a shared decision‐making process.

238 The risk of keratinocyte carcinoma (KC) in psoriasis patients receiving biologic therapy compared to conventional systemic therapy: Results from The British Association of Dermatologists Biologic Interventions Register (BADBIR)

Whether psoriasis patients exposed to biologic therapies have an elevated risk of KC (basal cell carcinoma [BCC] or cutaneous squamous cell carcinoma [cSCC]) remains uncertain. The aim of the present study was to determine whether such patients were at higher risk of developing a KC compared to those on conventional therapy. BADBIR, a pharmacovigilance register of psoriasis patients, explores the long-term safety of systemic therapies. Patients with chronic plaque psoriasis registering to BADBIR on their first biologic or a conventional therapy, who had at least one follow-up completed were included in analyses if they were of white ethnicity, Fitzpatrick skin types 1-4 and reported no previous cancers. Confounding factors included: age; sex; smoking; and previous exposure to acitretin, psoralen ultraviolet-A (PUVA), ciclosporin, and/or PUVA and ciclosporin. Propensity score-weighted Cox-proportional hazard models estimated the hazard ratio (HR) for developing a first KC or separately, first BCC or cSCC. In total, 5672 patients initiating biologic therapy and 3188 patients on conventional therapy who met the entry criteria were identified with 20558 and 7829 person-years of follow-up, respectively. During follow-up, 74 (1.3%) patients initiating a biologic therapy were diagnosed with their first KC (43 BCC; 34 cSCC first) and 22 (0.7%) patients receiving conventional therapy with their first KC (15 BCC; 10 cSCC first). No significant difference in risk was observed for developing a KC (adjusted HR 1.05; 95% CI 0.64, 1.73), BCC (0.84; 95% CI 0.45, 1.54) or cSCC (1.20; 95% CI 0.57, 2.50) on biologic compared to conventional therapy. In conclusion, biologic therapy does not appear to confer a higher risk of developing a first KC as compared to conventional therapy in psoriasis patients. These data will help inform clinical decision making in psoriasis patients at risk of KC in whom biologic or conventional therapy is being considered.

509 Association between biologics and major cardiovascular events in adult patients with plaque psoriasis: A cohort study in the British Association of Dermatologists Biologic Interventions Register (BADBIR)

509 Association between biologics and major cardiovascular events in adult patients with plaque psoriasis: A cohort study in the British Association of Dermatologists Biologic Interventions Register (BADBIR)

510 Development and validation of a risk prediction model for serious infection in patients with psoriasis using the British Association of Dermatologists Biologic Interventions Register (BADBIR)

510 Development and validation of a risk prediction model for serious infection in patients with psoriasis using the British Association of Dermatologists Biologic Interventions Register (BADBIR)

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

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. 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. 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. (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. 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. Clinical trial effectiveness and safety outcomes are not representative of real-world patients in BADBIR patients categorized as ineligible for such trials.

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

Psoriasis is a skin condition that leads to inflammation, resulting in red, scaly skin. Biologic therapies are very powerful treatments for psoriasis, but unfortunately, they have significant effects on the immune system, which may increase the possibility of getting cancers. The authors of this study analysed previous research (until August 2016) that looked at whether patients with psoriasis who received biologic therapies got more cancers compared to other patients. Some studies found that there was an increase in certain types of skin cancers, called non‐melanoma skin cancers (NMSC). There was no increase in any other types of cancers in the studies. However, the authors recognised several weaknesses in the studies, which could have affected the results. More research is needed to know whether there really is an increased risk of skin cancer with biologic treatment. Patients participating in long term studies such as the British Association of Dermatologists Biologic Interventions Register (BADBIR) will help to answer this important question.

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.

Risk of Serious Infection in Patients with Psoriasis Receiving Biologic Therapies: A Prospective Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

Serious infection is a concern for patients with psoriasis receiving biologic therapies. We assessed the risk of serious infections for biologics used to treat psoriasis by comparison with a cohort receiving non-biologic systemic therapies in a propensity score-weighted Cox proportional hazards model using data from the British Association of Dermatologists Biologic Interventions Register. Overall, 1,352; 3,271; and 994 participants were included in the etanercept, adalimumab, ustekinumab cohorts, respectively, and 3,421 participants were in the non-biologic cohort. A total of 283 patients had a serious infection; the incidence rates with 95% confidence intervals (CI) per 1,000 person-years were as follows: non-biologic, 14.2 (11.5–17.4); etanercept, 15.3 (11.6–20.1); adalimumab, 13.9 (11.4–16.6); and ustekinumab, 15.1 (10.8–21.1). No significant increases in the risk of serious infection were observed for etanercept (hazard ratio [HR] = 1.10, 95% CI = 0.75–1.60), adalimumab (HR = 0.93, 95% CI = 0.69–1.26), or ustekinumab (HR = 0.92, 95% CI = 0.60–1.41) compared with non-biologic systemic therapies or methotrexate-only (etanercept: HR = 1.47, 95% CI = 0.95–2.28; adalimumab: HR = 1.26, 95% CI = 0.86–1.84; ustekinumab: HR = 1.22, 95% CI = 0.75–1.99). The risk of serious infection should not be a key discriminator for patients and clinicians when choosing between non-biologic systemic therapies, etanercept, adalimumab, and ustekinumab for the treatment of psoriasis.

001 Risk of serious infection associated with biologic therapies in psoriasis: A prospective cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

001 Risk of serious infection associated with biologic therapies in psoriasis: A prospective cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

Patterns of biologic therapy use in the management of psoriasis: cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

Treatment modifications, including dose escalations, dose reductions, switches, discontinuations and restarts of biologics may be necessary in the management of psoriasis but the patterns of usage are incompletely defined. To examine the treatment utilization patterns of adalimumab, etanercept and ustekinumab among biologic-naïve and non-naïve patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register (BADBIR). The study cohort included adults with chronic plaque psoriasis who were followed up for ≥ 12 months. Treatment modifications were assessed during the first year of therapy. The time-trend method, comparing the cumulative dose (CD) patients received with the recommended cumulative dose (RCD), was used to assess dosing patterns. Concomitant use of other systemic treatments was also examined. In total, 2980 patients (adalimumab: 1675; etanercept: 996; ustekinumab: 309) were included; 79·2% were biologic-naïve. Over 12 months, 77·4% of patients continued the biologic, 2·6% restarted therapy after a break of ≥ 90 days, 2·5% discontinued, and 17·5% switched biologic therapy. Most patients (85·7%) received the RCD of the biologic, although 8·1% were exposed to a higher CD. In total, 749 (25·1%) patients used conventional systemic therapies concomitantly with a biologic at some stage; methotrexate was used most commonly (458; 61·2%). Of those using combination therapy, 454 (60·6%) continued the use of the conventional systemic therapy for > 120 days after the start of the biologic. More than one-third of patients experienced treatment modifications within the first year of initiating a biologic. Conventional systemic therapies, particularly methotrexate, were commonly used concurrently, which should be considered when evaluating treatment response and adverse events to biologics in real-world observational studies.

Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

Drug survival reflects a drug's effectiveness, safety, and tolerability. We assessed the drug survival of biologics used to treat psoriasis in a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR)). The survival rates of the first course of biologics for 3,523 biologic-naive patients with chronic plaque psoriasis were compared using survival analysis techniques and predictors of discontinuation analyzed using a multivariate Cox proportional hazards model. Data for patients on adalimumab (n=1,879), etanercept (n=1,098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.09-1.37), being a current smoker (HR 1.19; 95% CI: 1.03-1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI: 1.00-1.02) were predictors of discontinuation. Presence of psoriatic arthritis (HR 0.82; 95% CI: 0.71-0.96) was a predictor for drug survival. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45-1.84) or infliximab (HR 1.56; 95% CI: 1.16-2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37-0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival. The results of this study will aid clinical decision making when choosing biologic therapy for psoriasis patients.

Demographics and disease characteristics of patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register.

The British Association of Dermatologists Biologic Interventions Register (BADBIR) is a prospective, observational cohort designed to assess the long-term safety of biologic and conventional systemic therapies used for adults with moderate-to-severe psoriasis in the U.K. and Republic of Ireland. To describe the demographics, disease severity and comorbidities of patients with psoriasis on enrolment into BADBIR, and to highlight differences in those commencing biologics compared with those on conventional systemic therapies. Baseline data were collected from 151 dermatology departments in the U.K. and Republic of Ireland. Descriptive analysis was conducted. As of August 2014, 8399 patients were registered with BADBIR; 5065 (60%) received biologics, of whom 52·8% received adalimumab, 24·6% etanercept, 18·7% ustekinumab and 3·9% infliximab. In the comparator cohort 44·1% received methotrexate, 23·1% ciclosporin, 18·0% acitretin and 7·6% fumaric acid esters. Overall 4897 (58%) were male. Patients on biologics had a higher mean±SD age and disease duration than patients on conventional systemic therapies (46·3±12·7 vs. 44·3 ±14·3 years and 23·0± 12·6 vs. 19·0± 13·4years, respectively; both P<0·001). Mean body mass index, Psoriasis Area and Severity Index and Dermatology Life Quality Index scores for patients on biologics were higher than for those on conventional systemic therapies (31·0± 7·2 vs. 30·1±7·3kgm(-2) ; 16·4±8·3 vs. 15·5±7·9 and 17·4±7·5 vs. 15·0±7·1, respectively; all P<0·001). In total 71% of all patients had comorbidities and 47% had more than one comorbidity. The most frequent comorbidities were obesity (42·1%), hypertension (25·7%), depression (22·1%) and psoriatic arthritis (17·1%). BADBIR is an invaluable resource to study the safety and effectiveness of both biologic and conventional systemic therapies. Understanding differences in baseline characteristics between cohorts is crucial in undertaking future pharmacovigilance studies.

The British Association of Dermatologists’ Biologic Interventions Register (BADBIR): design, methodology and objectives

The British Association of Dermatologists (BAD) established a web-based pharmacovigilance register to assess the long-term safety of biologics prescribed for patients with severe psoriasis in September 2007. The BAD Biologic Interventions Register (BADBIR) also participates in the network of European psoriasis biologics registers (Psonet). This prospective observational cohort study compares adult patients with psoriasis treated with biologics vs. a comparator group exposed to conventional systemic therapies. Following baseline data acquisition, clinicians record changes in therapy, disease activity and adverse events for 5years (6-monthly for 3years, then annually thereafter). Patient details are flagged lifelong on the National Health Service Information Centre system to capture occurrence of malignancy or death. Primary study endpoints include malignancy, infection, serious adverse events and death. Collection of long-term effectiveness data is a subsidiary aim. By November 2011, the number of dermatology centres actively recruiting across the U.K. and Republic of Ireland had risen to 108 and a further 37 were actively engaged in the set-up process. Of the 3176 patients enrolled in the study to date, 2193 were registered within the biologic cohort and 983 in the conventional systemic (nonbiologic-exposed) cohort. A robust, high-quality, web-based register of biologic and conventional therapy for psoriasis has been established in the U.K. This is the largest project undertaken by the BAD. The data it will provide over the coming years will be invaluable to the safe use of biologics in clinical practice. A U.K.-wide dermatology clinical research network has been established that provides a framework for future studies in other diseases.

British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009

St John’s Institute of Dermatology, King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, London SE1 9RT U.K. *Department of Dermatology, Royal Gwent Hospital, Newport NP20 2UB, U.K. Department of Dermatology, Western Infirmary, Glasgow G11 6NT, U.K. The Dermatology Centre, Salford Royal Hospital, University of Manchester, Manchester Academic Health Science Centre, Manchester M6 8HD, U.K. §Psoriasis and Psoriatic Arthritis Alliance, PO Box 111, St Albans AL2 3JQ, U.K. –Department of Dermatology, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, U.K. **Royal National Hospital for Rheumatic Diseases, Bath BA1 1RL, U.K. Department of Dermatology, Belfast City Hospital, Belfast BT9 7AB, U.K. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K. §§Department of Dermatology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB9 2ZB, U.K.