Reduced doses of biological therapies in psoriasis: a new potentially “sustainable” frontier of psoriasis treatment

KEYWORDS:

• Psoraisis
• biologics
• biological therapy
• dose de-escalation
• dose spacing
• cost-effectiveness
• dose escalation
• skin

1. Introduction

In biological therapy, dose modification in carefully selected patients when psoriasis is in remission can reduce both treatment costs and the risks associated with drug exposure, a decision that should be made regardless of the duration of treatment [1]. The safety and cost-effectiveness of biologics should be incorporated in the physician-patient shared decision-making process not only in psoriasis but also in other types of inflammatory diseases [2].

2. Dose de-escalation

Recent studies postulate that seeking the minimal necessary doses using an optimized off-label dose-reduced regimen might improve the risk benefit/ratio and maximize clinical outcomes while reducing the costs of biologic treatment [3].

Such a dosing regimen differs from that recommended in the Summary of Product Characteristics and currently represents an off-label dosing regimen in psoriasis that lacks defined and accepted administration protocols. This strategy can improve the risk/benefit ratio of the drug by trying to use the minimal dose needed to obtain a good response with a potential reduction of adverse effects. Risk of infection, for example, depends on the dose in addition to the patient’s comorbidities. Recent rheumatological evidence suggests that sustained remission or low disease activity is more attainable with dose reduction compared to outright discontinuation of biologic therapy [4]. Moreover, maximizing clinical outcomes with minimum costs is crucial to relieve the burden on healthcare systems.

3. Dose escalation

A so-called ‘escalated dose strategy’ is the opposite of dosage tapering. Dose escalation or intensification includes shortening the scheduled dosing interval and/or increasing the amount of medication per single dose. In patients treated with etanercept, adalimumab, and ustekinumab, dose escalation in non-responders can result in greater efficacy compared with standard dosing [5]. Other evidence has demonstrated that dose escalation is associated with shorter drug survival rates since good control of the disease is lost, and it is not cost-effective [3]. Thus, it will not be described in this editorial.

Proper selection of patients who are candidates is mandatory before adjusting the dosage. The major aims in patients with psoriasis are maintenance of long-term drug survival [6] in order to keep the disease under control, maintain the improvement in quality of life, reduce the risk of appearance or progression of comorbidities (such as psoriatic arthritis), and reduce the costs of the therapy.

4. De-escalable populations

No proper definition of a good candidate for a reduced dose regimen has been reported. On the basis of our experience, we consider super-responder [7] patients who maintain PASI (psoriasis area severity index) 100 at 6 months from the beginning of therapy, as well as patients who have responded more slowly and maintain clear skin for at least 6 months to be good candidates. It has been demonstrated for almost all biologics that the rapidity and maintenance of response is higher in patients who are bionaive and thus better candidates for a reduced dose, even if failure of one line of therapy should not be considered as an exclusion criterion.

Psoriasis phenotype is a proxy of response in treatment, leading to a dose tapering strategy. Thus, we suggest to prefer patients with long-lasting psoriasis, without involvement of difficult-to-treat sites (scalp, nail, genital, palmoplantar), low BMI (body mass index), and absence of psoriatic arthritis or metabolic syndrome as candidates. PASI at the start of biologic treatment should not influence the decision of tapering the dosage after achieving PASI100, since higher PASI is often more represented among bionaive super-responder patients [7]. Baniandres et al. suggested that patients who received reduced doses had significantly longer-standing disease and longer treatment duration with the same biologic agent [1]. Patients with arthritis were not good candidates for dose adjustments. Smokers should be considered to be at greater risk of failing dose tapering given the high systemic level of inflammation [1].

5. Expert opinion

The most suitable candidates are those on an anti-IL-23 agent (risankizumab, tildrakizumab, guselkumab), since the pharmacokinetics of these drugs allows for longer drug administrations compared to anti-IL-17 agents. An anti-IL-23 agent could potentially be administrated if rebound of the disease is seen after an optimal response, thus starting to consider patients as ‘cured’ or ‘almost cured.’ This is reported to be a safe procedure in pilot studies, demonstrating that biologics are directed to tumor resident T cells where they can modify the disease, maintaining a response for months after discontinuation of the drug [8]. This has been associated with a reduction in CD69+, CD103+, and CD48+ tumor resident T cells in plaques after treatment with an anti-IL-23 agent [9]. Some authors proposed serum drug concentration as a possible indicator of dose escalation or dose de-escalation. In detail, these authors proposed escalation of the dosage if the serum levels of a specific biological drug are low and dose de-escalation if the levels are high according to a specific threshold [10].

Based on the half-life of the drug, we propose dose reduction by increasing the time between doses by 1.5-fold for risankizumab and tildrakizumab, while the time between doses for guselkumab can be prolonged for up to twice that recommended. Because no data have been reported for tildrakizumab and risankizumab de-escalation, differently from guselkumab, caution is needed in doubling the time for this treatment. In order to be safe, we just suggest to increase this by 1.5 fold.

For anti-IL-17 agents, the half-life of secukinumab and ixekizumab is shorter, and relapse is seen more frequently (despite greater rapidity in onset) when withdrawing the drug. These drugs are usually administered once a month, and it could be reasonable to taper to 1.5 times that, or 6 weeks, in patients who are good candidates. Brodalumab, given its receptor pharmacodynamics, appears to be a difficult candidate for tapering. Moreover, since bimekizumab has been available only recently, a potential tapering regimen remains unclear.

With regard to anti-TNF-alpha agents, therapeutic prolongation, although possible, does not appear advisable in view of the difficulties of recovering therapeutic response in the event of reduced effectiveness and the increased risk of developing anti-drug antibodies.

6. Conclusion

In conclusion, dose tapering may be sustainable in selected patients, and further investigation is advisable.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.