Strategies for switching therapy from classical immunosuppressants to dupilumab.

The addition of the highly effective biologic dupilumab to the spectrum of systemic treatment options raises questions about how to proceed when switching therapies. A team of experts has developed recommendations for clinical practice in which they point out what to pay attention to when switching from classic immunosuppressants to treatment with dupilumab.

With a worldwide prevalence of 2-5%, atopic eczema is one of the most common dermatoses [1]. In addition to basic therapy with various moisturizing and refatting topical agents, anti-inflammatory topical preparations are available for acute symptoms and, depending on the case, also antifungal and antibacterial substances. Systemic therapy may be required for moderate and severe forms of the disease. The systemic therapy with the biologic Dupilumab (Dupixent®), which has recently been approved for adult patients in Switzerland, has demonstrated an excellent efficacy-safety profile in clinical trials for the treatment of moderate to severe atopic dermatitis and is recommended as first-line therapy in the current guidelines (box) [2,3,13]. The other guideline-based treatment options for this indication, such as ciclosporin (first-line) and the preparations methotrexate, azathioprine, and mycophenolate mofetil, which can be used off-label, as well as systemic glucocorticosteroids, are not optimally suited for long-term therapy of atopic dermatitis due to the risk of side effects, according to the conclusion of a group of dermatological experts, who developed a recommended course of action for the switch to dupilumab on the basis of a literature review [4]. Wohlrab et al. point out in the corresponding article that, in addition to the reason for a change in therapy, such as lack of efficacy, undesirable side effects or contraindications, pharmacological circumstances must also be taken into account [4].

Change of system therapy can have different reasons

If, after a treatment period of 12-16 weeks, no or too low treatment effects are achieved in the recommended dose range (e.g., failure to achieve an EASI-50), this is referred to as insufficient efficacy. A secondary reduction in efficacy during the course of treatment may also be an argument for a change in therapy to dupilumab. Other possible reasons are undesirable treatment-related side effects (ADRs) or contraindication [5]. With regard to a clinically and pharmacologically sound action strategy, several factors must be considered, according to Wohlrab et al. [4]. The overriding principle is to prevent harm to the patient, whereby the risks lie on the one hand in the occurrence of undesirable drug effects during the change in therapy and on the other hand in an increase in disease activity. Since there are currently hardly any empirical data regarding the change of therapy to dupilumab , the recommendations of Wohlrab et al. are based on the results of the study. based on a combination of literature review, pharmacological considerations, and their experience [4].

Differences in pharmacokinetic elimination behavior.

Monoclonal antibodies differ pharmacokinetically with respect to elimination behavior from that of small-molecule drugs such as ciclosporin, methotrexate, azathioprine, and mycophenolate mofetil/mycophenolic acid derivatives [6]. While inactivation of small-molecule drugs occurs by renal or hepatic elimination or by metabolization in other tissues, clearance of monoclonal antibodies is based on binding to the target epitope (“antigen sink”), by proteolysis after uptake by cells of the reticuloendothelial system (e.g. macrophages) or by nonspecific endocytosis and subsequent lysosomal degradation. A chemical interaction between small-molecule drugs and monoclonal antibodies is therefore unlikely and, from a pharmacokinetic point of view, a coapplication of the two substance groups is therefore not critical [7].

Dupilumab reaches peak serum concentration and absolute bioavailability of approximately 64% 7-10 days after subcutaneous administration. The formation of endogenous antibodies against dupilumab with a neutralizing effect (so-called “anti drug antibodies”, ADA) was only observed to a very small and clinically irrelevant extent of about 0.5-2% [8].

Short-term parallel use with immunosuppressants possible

It is common for dupilumab to be initiated in patients who are still on therapy with immunosuppressants, particularly ciclosporin. For such a therapy switch from ciclosporin to dupilumab, combined use for 4-6 weeks could be considered, said Wohlrab et al. [4]. So far, there is no evidence for a longer-term combined use of a conventional immunosuppressant with dupilumab. Since no direct drug interactions with one of the already mentioned “small molecules” are to be expected with the use of Dupilumab, there would be no reservations from a pharmacological point of view against an immediate, indication-appropriate follow-up therapy or a combined use of Dupilumab with one of the conventional immunosuppressants (ciclosporin, systemic glucocorticoids, methotrexate, azathioprine or mycophenolic acid derivatives).

Ciclosporin: If switching to dupilumab is considered due to lack of efficacy of ciclosporin at a dose of 5 mg/kg bw/day for 12-16 weeks or due to UAWs that cannot be tolerated or compensated over time, treatment with dupilumab should be started immediately after discontinuation of ciclosporin without a break in therapy (Fig. 1) [4]. However, if switching to dupilumab is considered due to tolerable or even compensated ADRs over time or if ciclosporin is used for 1-2 years to avoid ADRs, ciclosporin should be given at the established dose for 4-6 weeks overlapping dupilumab therapy to avoid rapid recurrence of atopic dermatitis (Fig. 1) [4].

Methotrexate, azathioprine, or mycophenolic acid derivatives: If a change in therapy is considered for the off-label agents methotrexate, azathioprine, mycophenolate mofetil/mycophenolic acid derivatives due to lack of efficacy or occurrence of relevant ADRs, discontinuation should occur without tapering. Dupilumab therapy can be started immediately afterwards without a break in therapy. Although a temporal overlap by combination administration over 4-6 weeks is pharmacokinetically uncritical, it does not seem reasonable because of the longer effect half-lives, since a rapid relapse is not to be expected, according to Wohlrab et al. [4].

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