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

Clinical Implications•Data on drug survival can influence the choice of biologics for psoriasis.•Assessment of both drug discontinuation and dose escalation gives a more accurate measure of drug survival.•In this study, secukinumab is associated with higher drug survival versus adalimumab and ustekinumab.View Large Image Figure ViewerDownload Hi-res image Download (PPT) •Data on drug survival can influence the choice of biologics for psoriasis.•Assessment of both drug discontinuation and dose escalation gives a more accurate measure of drug survival.•In this study, secukinumab is associated with higher drug survival versus adalimumab and ustekinumab. Drug survival is used to assess the real-world efficacy of biologic drugs, acting as a proxy measure of drug effectiveness, tolerability, and safety. These real-world data are recognized as a complementary and valuable addition to randomized clinical trial results, which do not reflect drug performance in the routine clinical setting. The traditional model for biologic drug survival studies applies the binary outcome of drug discontinuation as the measure of drug survival. In their linked article, “Drug survival of adalimumab, secukinumab, and ustekinumab in psoriasis as determined by either dose escalation or drug discontinuation during the first 3 years of treatment – a nationwide cohort study,” Thein et al., 2023Thein D. Rosenø N.A.L. Maul J.T. Wu J.J. Skov L. Bryld L.E. et al.Drug survival of adalimumab, secukinumab, and ustekinumab in psoriasis as determined by either dose escalation or drug discontinuation during the first 3 years of treatment – a nationwide cohort study.J Invest Dermatol. 2023; ([e-pub ahead of print]) (accessed June 2, 2023)https://doi.org/10.1016/j.jid.2023.04.009Google Scholar present their findings when using either off-label dose escalation or drug discontinuation as a measure of biologic drug survival. The increase in detail that this analysis provides allows for the assessment of both on-label and off-label drug effectiveness, thereby providing more information to the prescribing clinician. The prescribing of biologic drugs has become increasingly complex with the rise in off-label dosing regimens (Gambardella et al., 2021Gambardella A. Licata G. Sohrt A. Dose adjustment of biologic treatments for moderate-to-severe plaque psoriasis in the real world: a systematic review.Dermatol Ther (Heidelb). 2021; 11: 1141-1156Google Scholar). For example, serum adalimumab measurement and increasing dosing frequency to weekly can be an effective strategy when standard adalimumab fortnightly dosing is ineffective (Hussain et al., 2023Hussain A.B. Havelin A. Ball S. Weatherhead S. Reynolds N.J. Hampton P. Increasing to weekly adalimumab dosing leads to improved psoriasis outcomes-a retrospective single-centre review of real-world data.J Eur Acad Dermatol Venereol. 2023; 37: e527-e528Google Scholar). A similar approach of ustekinumab dose escalation is now frequently adopted as per guidelines when effect is lacking (Warren et al., 2015Warren R.B. Smith C.H. Yiu Z.Z.N. Ashcroft D.M. Barker J.N.W.N. Burden A.D. et al.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).J Invest Dermatol. 2015; 135: 2632-2640Google Scholar). In addition, the reassuring safety profile of biologic drugs has increased the coprescribing of systemic medications and phototherapy with biologics (Iskandar et al., 2017Iskandar I.Y.K. Ashcroft D.M. Warren R.B. Evans I. McElhone K. Owen C.M. et al.Patterns of biologic therapy use in the management of psoriasis: cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).Br J Dermatol. 2017; 176: 1297-1307Google Scholar). Consequently, assessing the true drug effect of an individual biologic can be challenging. Biologic drug survival is perceived as a good proxy measure of drug effectiveness and safety; however, several under-recognized factors may also contribute to the decision to discontinue a biologic, including new comorbidity diagnoses such as psoriatic arthritis, patient preference, compliance with frequent dosing regimens, drug cost, and drug availability (including the availability of dose escalations). Therefore, drug survival likely reflects a more complex interplay of factors influencing drug prescribing. In the linked article, the authors summarize the results of previous real-world drug survival studies in psoriasis, which showed higher drug survival of ixekizumab, guselkumab, secukinumab, and ustekinumab than of adalimumab and higher drug survival overall in biologic-naive patients. Ustekinumab has previously been reported to have a longer drug survival than TNF and IL-17 inhibitors (Mourad and Gniadecki, 2021Mourad A.I. Gniadecki R. Biologic drug survival in psoriasis: a systematic review & comparative meta-analysis.Front Med (Lausanne). 2021; 7625755Google Scholar). They emphasize the inadequacies of representing drug survival through a binary measurement of drug discontinuation and, instead, examine biologic performance by assessing time to either off-label dose escalation (shortening dose interval or increasing dose) or discontinuation. The study cohort was from DERMBIO, a Danish national psoriasis patient registry, including adult patients with plaque psoriasis prescribed either adalimumab, guselkumab, ixekizumab, secukinumab, or ustekinumab (3,559 patients, 38.8% women, mean age of 46.0 years). Three outcomes were evaluated: composite endpoint of either off-label dose escalation or drug discontinuation, dose escalation alone, and drug discontinuation alone. The primary outcome (discontinuation or dose escalation of biologic therapy) was reached by 2,463 (57.1%) patients. The probability of achieving this endpoint within the first 52 weeks was lowest for secukinumab (28.4%) and highest for ustekinumab (39.6%) than 36.7% for adalimumab. Biologic-naive patients were less likely to reach the composite endpoint. When Cox regression models were adopted, secukinumab was associated with a lower risk of the composite endpoint than ustekinumab (hazard ratio [HR] = 0.66, 95% confidence interval [CI] = 0.59–0.76) versus a higher risk with adalimumab (HR = 1.15, 95% CI = 1.05–1.26). So, a higher proportion of patients on secukinumab remained on an on-label dosing regime. Biologic dose was escalated in 520 (12.1%) treatment series, with ustekinumab showing the highest risk (11.2% within 20 weeks) and secukinumab showing the lowest. The reason most patients underwent ustekinumab dose escalation was due to higher patient weight (74.5%). Drug discontinuation occurred in 50.6% of the treatment series, with the lowest and highest median times to discontinuation noted in secukinumab (37 weeks) and ustekinumab (53 weeks) groups, respectively. The risk of discontinuation, assessed with a Cox regression model, was lowest for ustekinumab. In summary, the authors have shown that secukinumab was associated with a higher drug survival assessed by their composite endpoint than ustekinumab and adalimumab, contrary to previously published observational studies (Mourad and Gniadecki, 2021Mourad A.I. Gniadecki R. Biologic drug survival in psoriasis: a systematic review & comparative meta-analysis.Front Med (Lausanne). 2021; 7625755Google Scholar; Lunder et al., 2019Lunder T. Zorko M.S. Kolar N.K. Suhodolcan A.B. Marovt M. Leskovec N.K. et al.Drug survival of biological therapy is showing class effect: updated results from Slovenian National Registry of psoriasis.Int J Dermatol. 2019; 58: 631-641Google Scholar). Secukinumab drug survival further increased in biologic-naive patients, suggesting that secukinumab may be most effective as a first-line biologic. Using their composite endpoint, they note a considerably lower drug survival for ustekinumab than in previous studies (Lunder et al., 2019Lunder T. Zorko M.S. Kolar N.K. Suhodolcan A.B. Marovt M. Leskovec N.K. et al.Drug survival of biological therapy is showing class effect: updated results from Slovenian National Registry of psoriasis.Int J Dermatol. 2019; 58: 631-641Google Scholar; Warren et al., 2015Warren R.B. Smith C.H. Yiu Z.Z.N. Ashcroft D.M. Barker J.N.W.N. Burden A.D. et al.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).J Invest Dermatol. 2015; 135: 2632-2640Google Scholar). They acknowledge that the flat pricing structure of ustekinumab in Denmark and the perception that dose escalation is safe may have contributed to this. Through this novel study, the authors draw attention to the complexities of assessing real-world biologic drug effectiveness and safety. They rightly acknowledge the limitations of their paper, including a significantly smaller secukinumab patient group, potential missing data bias, and lack of data on clinical reasoning for dose escalation. However, there are additional limitations to note. It is unclear from the paper how readily dermatologists in Denmark escalate the dose of secukinumab. In the United Kingdom (UK), a dose of 300 mg monthly is commenced after loading, and guidelines recommend discontinuation rather than dose escalation of secukinumab if a response has not been achieved by 12 weeks. Therefore, in the UK, secukinumab dose adjustments are very rare. Clarity on whether this is also the case in Denmark and thus a source of bias would be helpful. The authors could carry out further analysis of their findings, including evaluating the role of relevant patient factors (other than previous biologic status), such as comorbidities, sequence of previous biologics, and previous systemic therapy. This could highlight possible variations in clinical response between patient groups when using their approach to assess biologic drug survival. This paper highlights the increasing ambition of dermatologists to use a personalized medicine approach for patients with treatment-refractory psoriasis. The authors (Thein et al., 2023Thein D. Rosenø N.A.L. Maul J.T. Wu J.J. Skov L. Bryld L.E. et al.Drug survival of adalimumab, secukinumab, and ustekinumab in psoriasis as determined by either dose escalation or drug discontinuation during the first 3 years of treatment – a nationwide cohort study.J Invest Dermatol. 2023; ([e-pub ahead of print]) (accessed June 2, 2023)https://doi.org/10.1016/j.jid.2023.04.009Google Scholar) report that 35% of patients prescribed ustekinumab were adjusted to an off-label dose. The ability to make such adjustments will vary between countries and clinics on the basis of drug costs, regulations, and physician attitudes; however, the enthusiasm to move away from licensed dosing schedules is clear. Coadministration of biologic drugs with other treatments such as methotrexate, acitretin, apremilast, or phototherapy is also common. Few dermatologists have embraced dual biologic treatment plans. This is due to a combination of financial limitations and uncertainties over the consequences of more broad-based immunosuppression. As more drugs move to biosimilar versions, careful trials of combination biologics may become financially feasible and could deliver significant benefits to complex patients with currently uncontrolled disease. Careful evaluation of safety and outcomes will be needed. As shown by this study, despite the increasing number of licensed biologic therapies, a significant proportion of patients do not achieve skin clearance, leading to biologic dose escalation or discontinuation. There are few factors to steer the choice of biologic, other than contraindications and cost. Consequently, a trial-and-error approach is adopted, which can lead to patients trialing several biologics before achieving disease control. The coadministration of other medications adds to the complexity and increases the challenge of evaluating which therapies are working effectively. There is therefore a considerable unmet need for a more targeted approach to biologic prescribing, as shown by the significant resource directed toward psoriasis biomarker discovery (Foulkes et al., 2019Foulkes A.C. Watson D.S. Carr D.F. Kenny J.G. Slidel T. Parslew R. et al.A framework for multi-omic prediction of treatment response to biologic therapy for psoriasis.J Invest Dermatol. 2019; 139: 100-107Google Scholar). An alternative approach could be the application of artificial intelligence to predict patient outcomes using psoriasis registry data. Machine learning approaches to evaluate psoriasis treatment outcomes are already being published (Havelin and Hampton, 2022Havelin A. Hampton P. Telemedicine and e-health in the management of psoriasis: improving patient outcomes - a narrative review.Psoriasis (Auckl). 2022; 16: 15-24Google Scholar). Data volumes could be increased by combining registry data. However, to apply such methodology, measures of treatment success need to be clearly defined, and the relevant data to train such models must be complete within registries to reduce the risk of bias and poorly fitting models. The application of such methodology could also provide insight into the complexities behind the variation in clinical response to biologics, which remains poorly understood. In summary, this study has assessed drug survival by evaluating both drug discontinuation and dose escalation and has highlighted the growing complexities of biologic prescribing. By adopting this approach, secukinumab was associated with the highest drug survival, contrary to previously published biologic drug survival studies. This warrants further in-depth study, including replication in other psoriasis real-world datasets and a wider assessment of reasons for drug discontinuation and dose escalation. Amaani B. Hussain: http://orcid.org/0000-0002-3304-462X Philip J. Hampton: http://orcid.org/0000-0001-6797-2697 PJH has received educational grants from Novartis, Almirall, AbbVie, and UCB. PJH is a member of the British Association of Dermatologists Biologic and Immunomodulators Register (UK PsO biologics registry) steering committee. This is a commentary on “Drug survival of adalimumab, secukinumab, and ustekinumab in psoriasis as determined by either dose escalation or drug discontinuation during the first 3 years of treatment.” Drug survival of adalimumab, secukinumab, and ustekinumab in psoriasis as determined by either dose escalation or drug discontinuation during the first 3 years of treatment – a nationwide cohort studyJournal of Investigative DermatologyPreviewReal-world efficacy of biologics may be insufficiently assessed through common drug survival studies. The objective was thus to examine real-world performance of biologics in the treatment of psoriasis using the composite endpoint of either discontinuation or off-label dose escalation. Using a prospective nationwide registry (DERMBIO, 2007-2019), we included psoriasis patients treated with adalimumab, secukinumab, and/or ustekinumab, which have all been used as first-line therapy during the inclusion period. Full-Text PDF Open Access