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

Warren, Richard B; Marsden, Antonia; Tomenson, Barbara; Mason, Kayleigh; Soliman, Moetaza M.; Burden, A. D.; Reynolds, Nick J.; Stocken, Deborah; Emsley, Richard; Griffiths, Christopher E.M.; Smith, Catherine

doi:10.1111/bjd.16776

Cited by 80 publications

(96 citation statements)

References 28 publications

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“…25 A broadly similar approach to covariate selection was adopted to that taken by Zhu et al 25 , but also included factors known to influence response to biologics across the BADBIR cohort. 38 Covariates that we found to be significantly associated with clearance overlapped with those from the published model. 25 Of note, Zhu et al 25 reported a positive relationship between creatinine clearance and drug clearance, and in line with this we found increased serum creatinine concentration to be associated with reduced drug clearance (creatinine clearance values were not derived in our study).…”

Section: Key Findingsmentioning

confidence: 60%

“…A broadly similar approach to covariate selection was adopted to that taken by Zhu et al ,. but also included factors known to influence response to biologics across the BADBIR cohort . Covariates that we found to be significantly associated with clearance overlapped with those from the published model .…”

Section: Discussionmentioning

confidence: 94%

“…Although the latter two measurements were unavailable in our cohort, we also found clearance to be around 30% higher in diabetic vs. nondiabetic patients. Possible factors accounting for this include decreased lymphatic function, increased glycation of ustekinumab, and differences in body composition . However, diabetes was not included in the final model as its effect was accounted for by waist circumference.…”

Section: Discussionmentioning

confidence: 99%

“…Possible factors accounting for this include decreased lymphatic function, increased glycation of ustekinumab, and differences in body composition. 38,39 However, diabetes was not included in the final model as its effect was accounted for by waist circumference. Although we found higher bodyweight with a priori allometry to be the only covariate associated with increased volume of distribution, Zhu et al 25 additionally reported that diabetes and ethnicity were significant covariates.…”

Section: Key Findingsmentioning

confidence: 99%

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Using Real‐World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic‐Pharmacodynamic Study

Pan

Dand

Lonsdale

et al. 2020

Clinical Translational Sci

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Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real‐world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first‐line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti‐drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one‐compartment model. A maximum effect (Emax) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half‐maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring “dashboard” to individualize dosing and improve treatment outcomes.

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Section: Key Findingsmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Key Findingsmentioning

confidence: 99%

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Using Real‐World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic‐Pharmacodynamic Study

Pan

Dand

Lonsdale

et al. 2020

Clinical Translational Sci

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“…In a large multicentre study, Warren and colleagues investigated predictors of PASI 90 at 6 and 12 months following treatment initiation . Nonwhite ethnicity, female sex, smoking, unemployment, psoriasis of the palms and soles and the presence of small chronic plaques were associated with reduced odds of achieving PASI 90.…”

Section: Discussionmentioning

confidence: 99%

Complete skin clearance and Psoriasis Area and Severity Index response rates in clinical practice: predictors, health‐related quality of life improvements and implications for treatment goals

et al. 2019

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Summary Background Psoriasis Area and Severity Index (PASI) 90 is suggested to be the new standard endpoint for randomized controlled trials of biologics for psoriasis, whereas treatment guidelines often still refer to PASI 75. Objectives To analyse in a real‐world setting: firstly, what factors are associated with higher levels of treatment response to biologics; secondly, the health‐related quality of life gains associated with different response levels in clinical practice. Methods Biologically naïve patients with PASI, Dermatology Life Quality Index (DLQI) and EuroQol (EQ)‐5D outcomes before (maximum 6 months) and after (3–12 months) switch to biologics during registration in the Swedish National Registry for Systemic Treatment of Psoriasis (PsoReg) were included (n = 515). Patient characteristics associated with higher treatment response were analysed by regression analyses. Improvements in absolute PASI, DLQI and EQ‐5D were assessed in different PASI percentage response levels. Results High PASI percentage response was associated with higher PASI before switch and lower body mass index. DLQI and EQ‐5D improved within all responder groups (P < 0·001). The magnitude of improvements in DLQI (P = 0·02) differed between responder groups. The mean (SD) DLQI improvements for PASI 75<90 responders, PASI 90<100 responders and patients achieving complete skin clearance (PASI 100) were 9·9 (7·4), 11·5 (7·0) and 8·0 (6·1), respectively. Conclusions PASI percentage change is largely dependent on absolute PASI before switch. Patients in clinical practice lack ‘baseline’ PASI values as they may switch directly from one treatment to another or stay successfully treated for a longer time period. Treatment goals such as PASI 90 are thus not suitable for treatment guidelines or for follow‐up in clinical practice. What's already known about this topic? Randomized clinical trials of biologics as well as treatment guidelines include treatment goals based on a percentage improvement compared with baseline Psoriasis Area and Severity Index (PASI), such as PASI 75 or PASI 90. Few studies have assessed which factors are associated with high skin clearance rates, or health‐related quality of life (HRQoL) improvements associated with different levels of skin clearance in clinical practice. What does this study add? A high absolute PASI before switch to biologics and low body mass index are associated with higher PASI percentage response. Few patients with baseline PASI >30 achieved complete skin clearance (CSC). All responder groups achieved significant HRQoL improvements. Patients achieving CSC (PASI 100) had lower absolute PASI before switch and lower improvements in absolute PASI and HRQoL than patients with almost cleared skin. What are the clinical implications of this work? Relative measures based on PASI percentage, such as PASI 75 or PASI 90, are not suitable for treatment guidelines or for follow‐up in clinical practice.

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Association of Serum Ustekinumab Levels With Clinical Response in Psoriasis

et al. 2019

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; for the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) Study Group and the Psoriasis Stratification to Optimise Relevant Therapy (PSORT) Consortium IMPORTANCE High-cost biologic therapies have transformed the management of immune-mediated inflammatory diseases. To optimize outcomes and reduce costs, dose adjustment informed by measurement of circulating drug levels has been shown to be effective in various settings. However, limited evidence exists for this approach with the interleukin 12 and interleukin 23 inhibitor ustekinumab. OBJECTIVE To evaluate clinical utility of therapeutic drug monitoring for ustekinumab in patients with psoriasis. DESIGN, SETTING, AND PARTICIPANTS A prospective observational cohort of 491 adults with psoriasis was recruited to the multicenter Biomarkers of Systemic Treatment Outcomes in Psoriasis study within the British Association of Dermatologists Biologic and Immunomodulators Register from June 2009 to December 2017; samples from some patients were taken between 2009 and 2011 as part of a pilot study with the same inclusion criteria. EXPOSURE Serum ustekinumab level measured at any point during the dosing cycle using an enzyme-linked immunosorbent assay. MAIN OUTCOMES AND MEASURES Disease activity measured using the Psoriasis Area and Severity Index (PASI) score. Treatment response outcomes were PASI75 (75% reduction in PASI score from baseline [primary outcome]), PASI90 (90% reduction of PASI score from baseline), and absolute PASI score of 1.5 or less. RESULTS A total of 491 patients (171 women and 320 men; mean [SD] age, 45.7 [12.8] years) had 1 or more serum samples (total, 853 samples obtained 0-56 weeks from start of treatment) and 1 or more PASI scores within the first year of treatment. Antidrug antibodies were detected in only 17 of 490 patients (3.5%). Early measured drug levels (1-12 weeks after starting treatment) were associated with PASI75 response 6 months after starting treatment (odds ratio, 1.38; 95% CI, 1.11-1.71) when adjusted for baseline PASI score, age, and ustekinumab dose. However, this finding was not consistent across the other PASI outcomes (PASI90 and PASI score of Յ1.5). CONCLUSIONS AND RELEVANCE This real-world study provides evidence that measurement of early serum ustekinumab levels could be useful to direct the treatment strategy for psoriasis. Adequate drug exposure early in the treatment cycle may be particularly important in determining clinical outcome.

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

Abstract: Psoriasis phenotype and potentially modifiable factors are associated with poor outcomes with biologics, underscoring the need for lifestyle management. Effect sizes suggest that these factors alone cannot inform treatment selection.

Cited by 80 publications

References 28 publications

Using Real‐World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic‐Pharmacodynamic Study

Using Real‐World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic‐Pharmacodynamic Study

Complete skin clearance and Psoriasis Area and Severity Index response rates in clinical practice: predictors, health‐related quality of life improvements and implications for treatment goals

Association of Serum Ustekinumab Levels With Clinical Response in Psoriasis

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