"It's always an individual weighing".

For the treatment of moderate and severe atopic dermatitis, three oral Janus kinase inhibitors are now available in addition to two subcutaneously administered biologics. While the former specifically target individual inflammatory mediators, the latter block signal transduction in the cell. Which therapy option is best suited for which patient cannot be answered in a generalized way. Scientific evidence and empirical values serve as a basis for decision-making. Whereby it is always central to translate the findings into the best possible clinical benefit for the individual patient.

Looking at the pathogenesis of atopic dermatitis (AD), it becomes clear that it is important to treat the barrier disorder and the inflammation, because these factors also influence each other, explained Prof. Dagmar Simon, MD, Senior Physician, University Department of Dermatology, Inselspital Bern [1]. Type 2 immune responses not only represent the cellular correlate for skin inflammation, but also significantly influence barrier dysfunction and microbial dysbiosis [2,3]. The typical symptoms of AD are pruritus, dry skin, and chronic or recurrent eczematous house lesions in various predilection sites. In a proportion of AD patients, topical treatment alone (^TCSa, ^TCIb) proves insufficient and systems therapy is required to reduce the disease burden. Conventional systemic immunosuppressants such as ciclosporin are not always effective in this regard and have significant adverse side effects, particularly in long-term use [4,5].

^a TCS=Topical Corticosteroids
^b TCI=Topical Calcineurin Inhibitors.

Innovative Targeted System Therapeutics – Spoilt for Choice

For several years, biologics and small molecules with different efficacy spectra and safety profiles have been available for moderate to severe AD in addition to conventional systemic therapies. (Table 1). In order to decide whether to use a biologic or a JAK inhibitor in an AD patient, various advantages and disadvantages have to be weighed up, emphasized Prof. Simon [1]. Biologics interfere with the inflammatory process in AD by targeting individual cytokines (Fig. 1) [15]. Janus kinase (JAK) inhibitors, on the other hand, are small-molecule agents that target inhibition of the JAK/STAT pathway (Fig. 2) [15].

Dupilumab was the first biologic in the AD indication to receive approval in 2019, and another monoclonal antibody, tralokinumab, has been available for moderate-to-severe AD since 2022 [6]. While dupilumab inhibits IL-4 and IL-13 signaling via inhibition of IL-4Rα, tralokinumab targets IL-13 by preventing its binding to IL-13Rα1 and IL-13Rα2 [7]. Among JAK inhibitors, baricitinib (JAK1/2-i) and upadacitinib (JAK1-i) became available in 2021, followed by the approval of abrocitinib (JAK1-i) in 2022 [6].

Heterogeneity of AD patients causes different selection criteria.

AD exhibits great heterogeneity in clinical features, severity, and course [1]. In addition, AD is associated with interindividual differences in comorbidities. From the wealth of possible criteria that can be used in the treatment decision, Prof. Simon highlighted the following in particular [1].

Comorbidities – killing two birds with one stone: AD patients have an increased susceptibility to developing another atopic disease. Atopy is a genetically determined readiness to react to aerogenic, gastrointestinal or cutaneous contact with environmental substances with increased IgE formation. Dupilumab, in addition to AD, is also approved for the treatment of asthma and in chronic rhinosinusitis with nasal polyps. There are also findings that dupilumab improves eosinophilic esophagitis. “If there are comorbidities along those lines, I would probably lean most toward dupilumab,” the speaker explained [1]. There are also some small studies (e.g., case reports) showing an effect of JAK inhibitors in asthma, but the data are still limited.

That there is an association between AD and inflammatory bowel disease (IBD) is evident from scientific studies, i.e., patients with ulcerative colitis or Crohn’s disease are at higher risk for AD and vice versa [8]. In Crohn’s disease, immune responses mediated by type 1 T helper cells (Th1 cells) appear to dominate, in contrast to ulcerative colitis, in which the immune response is predominantly stimulated by Th2 cells [9]. Therefore, it may be that treatment with dupilumab or tralokinumab has beneficial effects on ulcerative colitis.

Atopic dermatitis is the most common comorbidity of alopecia areata [10]. Based on corresponding evidence of efficacy, the JAK inhibitor baricitinib was also approved for the indication alopecia areata [11]. “In the meantime, however, there are also data on dupilumab,” Prof. Simon said. At least for subgroups of alopecia patients, dupilumab may eventually be an effective therapy [12].

Safety profile – what are important implications? Janus kinases (JAK) mediate the action of numerous inflammatory cytokines and are known to increase the risk of infection as a side effect. Before starting therapy, in addition to ruling out chronic infectious diseases (e.g., hepatitis, tuberculosis), particular attention should be paid to herpes virus-associated infections (herpes simplex labialis, reactivation or primary infection with the varicella zoster virus) [13]. Nasopharyngitis, upper respiratory tract infections, and urinary tract infections also occur more frequently with treatment with JAK inhibitors [14]. Vaccination with inactivated vaccines is possible during treatment with JAK inhibitors [13].

Regarding dupilumab and tralokinumab, empirical data show that the safety profile is very good, Prof. Simon reported [1]. The most common side effects are local reactions at the injection site and conjunctivitis. “We know that quite a few patients develop conjunctivitis with dupilumab, but it should not be forgotten that AD patients are more likely to have ocular inflammation,” she said [1]. When considering dupilumab therapy in AD patients with a history of ocular inflammation, she often consults the ophthalmologist so that any conjunctivitis can be treated from the start of treatment.

To which age group does the patient belong? Dupilumab has a marketing authorization in Switzerland in the indication AD from 6 years of age [6]. Tralokinumab and the JAK inhibitors have so far only been approved in this country for AD patients over 18 years of age [6]. Often, AD patients tend to be young people. Therefore, in female patients, one must also consider which therapy would be possible during pregnancy (SS), the speaker points out [1]. JAK inhibitors are contraindicated because they are teratogenic. “No teratogenicity has been found with dupilumab,” said Prof. Simon [1]. The compendium cautiously states that dupilumab can also be given during SS within the framework of a risk-benefit assessment.

Dosage form: The dosage form can play an important role for patients, Prof. Simon acknowledged [1]. Dupilumab and tralokinumab are available as prefilled syringes. After the initial dose, patients receive one or two subcutaneous injections every two weeks. For adolescents, there is a weight-adapted dosing regimen.

Baricitinib, upadacitinib, and abrocitinib are available as film-coated tablets and can be taken once daily, independent of meals [6].

“Shared decision making”: involving patients in decision-making.

In addition to their high efficiency, the advantages of biologics include low toxicity. During the course of treatment, anti-drug antibodies may be formed, leading to secondary loss of efficacy. JAK inhibitors have attracted great interest mainly because of their rapid onset of action and peroral administration. Considering the safety profile, laboratory monitoring is required. Additional modern active ingredients are expected to be approved in the coming years. Numerous clinical trials are currently underway, including JAK inhibitors that can be applied directly to the skin as a cream. This would significantly reduce the risk of side effects. However, none of these substances has yet been approved. In conclusion, careful selection of the individually appropriate targeted treatment and adequate follow-up can improve the efficacy and safety of systemic AD therapy. Finally, Prof. Simon discusses the recent safety warnings on JAK inhibitors. “The warnings are largely based on studies and observations with tofacitinib in rheumatoid arthritis,” the speaker explained [1]. In the ORAL Surveillance study, the patient population studied was found to be at increased risk of thromboembolic disease and malignancy, and also at increased risk of serious cardiovascular disease and mortality. “To what extent this will prove true for selective JAK-1-/2-i remains to be seen,” said Prof. Simon [1].

Congress: Joint advanced training BE-BS-ZH

Literature:

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