Persistence and Effectiveness of Nonbiologic Systemic Therapies for Moderate-to-Severe Psoriasis in Adults

A Systematic Review

K.J. Mason; S. Williams; Z.Z.N. Yiu; K. McElhone; D.M. Ashcroft; C.E. Kleyn; Z.K. Jabbar-Lopez; C.M. Owen; N.J. Reynolds; C.H. Smith; N. Wilson; R.B. Warren; C.E.M. Griffiths

Disclosures

The British Journal of Dermatology. 2019;181(2):256-264. 

In This Article

Discussion

This systematic review found that in the treatment of moderate-to-severe plaque psoriasis the probability of drug survival at 1 year was 23% for ciclosporin, 42% for acitretin and 50% for methotrexate.[26] Discontinuations due to adverse events (42% FAE and 22% methotrexate,[27] 46% FAE,[31] 43% FAE,[33] 22% methotrexate)[28] were more common for FAE than for methotrexate. There were mixed results for discontinuations due to ineffectiveness (44% acitretin, 21% ciclosporin and 33% methotrexate;[26] 22% FAE).[32] No studies reported effectiveness outcomes for acitretin or ciclosporin. The persistence and effectiveness of FAE and methotrexate were better characterized, but mean discontinuation times ranged from 28 to 50 months (FAE)[27,31,32] and 7·7 to 22·3 months (methotrexate).[26–29] Proportions of patients achieving PASI 75 at 12 months were reported for FAE (76%)[30] and methotrexate (53%[28] and 59%),[29] with 76% of patients on FAE achieving a PGA of markedly improved or clear at 12 months.[32]

A significant limitation to the current literature investigating the persistence of systemic therapy is the lack of survival analyses. Survival analyses are essential when using observational methods to explore drug persistence, because without them, differing lengths of follow-up will not be accounted for. NICE recommends that ciclosporin use should not exceed 1 year unless patients have severe and/or unstable disease and biologic therapy is contraindicated. As ciclosporin is usually prescribed for short durations, the lack of long-term persistence should not be viewed as a proxy for poor safety or ineffectiveness of this therapy.[3] Of the eight studies identified, one conducted a survival analysis on the time to drug discontinuation for patients using each systemic therapy.[26] Three additional studies also conducted survival analyses; however, one pooled all systemic therapies into a systemic cohort,[29] the second reported treatment courses rather than patients,[27] and the third study did not provide the definition for discontinuation used in the survival analysis,[28] making the results difficult to interpret.

A further limitation to the studies exploring therapy persistence is the inconsistent definition of drug discontinuation. Of the seven studies reporting therapy persistence, four did not provide any definition of drug discontinuation.[29,31–33] One study defined discontinuation as 'a suspension of medication' due to a range of possibilities, however, it did not specify what a 'suspension' was or a time frame.[28] Two studies provided a sufficient definition of a discontinuation, providing a time frame for how long patients were not using therapy.[26,27] Due to the lack of, and difference in, a definition of discontinuation, it is difficult to ascertain whether short-term breaks in therapy have been accounted for. Definitions of drug discontinuation and time frames are particularly important when interpreting ciclosporin survival, as this is generally given for short periods of time.

Many of the included studies lack complete reporting and analysis of baseline characteristics. Evidence shows there are differences in the prescribing patterns of psoriasis therapies for different patients,[34] while the definition of moderate-to-severe psoriasis remains inconsistent, resulting in a range of baseline severities used between countries and healthcare systems. It would therefore be beneficial to assess the baseline characteristics of the therapy cohorts separately to identify differences between them. One study pooled the characteristics of the different therapy cohorts[29] and five studies did not report three or more of the baseline measurements listed.[27,28,30,32,33] This lack of detail makes the quality assessment both within and between studies more difficult.

There is little acknowledgment of prevalent-user bias throughout the current literature. A prevalent user can be defined as a patient who previously used the therapy of interest before the start of the study follow-up, then restarted the same therapy during the study period.[35] The inclusion of such patients within an analysis can bias results as they may have been exposed to a specific therapy previously and could be prescribed this again due to a previous positive response, or they could be exposed to a new therapy if their initial treatment failed. One study reported the proportion of incident users within the entire cohort and one reported the proportion of treatment courses that were first line,[27] while only four studies provided the proportions of incident users for individual therapies.[26,28,31,32] It would be beneficial to conduct sensitivity analyses with and without prevalent users to identify whether prevalent-user bias is present.

The discontinuation of previous therapy could also influence the disease severity recorded prior to initiating a new one, particularly if there are minimal washout periods or overlaps between them. By reporting both the aggregate estimates and estimates stratified by therapy, we can understand better whether previous therapy exposure affects drug persistence or effectiveness. Another factor that influences the persistence or effectiveness of therapies is medication adherence. Patients with psoriasis registering to BADBIR on acitretin, ciclosporin, FAE or methotrexate were almost twice as likely to be nonadherent (29·2%) as patients receiving etanercept or adalimumab (16·4%, P < 0·001).[36] Medication adherence should be assessed when investigating treatment response, particularly whether nonadherence is intentional (e.g. medication perceived to be ineffective) or unintentional (e.g. lower persistence related to habit strength).

The results of this review reflect the contemporary evidence for the persistence and effectiveness of systemic psoriasis therapies within the real-world environment. Since performing our database search, one conference abstract has been published as a manuscript. The authors performed a single-centre, retrospective study of 626 patients with psoriasis receiving FAE monotherapy, and demonstrated a median duration of therapy of 1·7 years, with 188 patients (30%) discontinuing therapy.[37] The introduction of biologic and small-molecule therapies in the past decade is likely to have influenced the persistence of acitretin, ciclosporin, FAE and methotrexate in clinical practice, which is yet to be addressed in the literature. Future analyses should stratify by year of initiation to account for changes in the prescribing environment and thus the persistence of these therapies over time.

The complexity of studying persistence and effectiveness of therapy in clinical practice is highlighted by the varying results, study cohorts and methods of reporting. The inconsistent methods of reporting prevented a meta-analysis from being conducted. There was also the potential to introduce bias via the outcome definition specified in the protocol for this systematic review. Although no studies were excluded based on outcome definition alone (Appendix S4; see Supporting Information), future reviews of this topic should consider the use of a more robust definition to minimize the risk of excluding a study that used a different but relevant outcome definition.

In conclusion, this systematic review highlights how evidence for the persistence and effectiveness of systemic therapies for psoriasis in clinical practice is lacking. There are few studies exploring acitretin or ciclosporin, and those that have examined FAE or methotrexate are difficult to compare due to incomplete reporting of baseline characteristics, insufficient survival analyses and differing definitions of drug discontinuation. There is therefore a need for good-quality observational research, with an additional need for uniform methods of analysis and reporting to allow for meta-analyses.

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