Successful tapering of dupilumab in patients with atopic dermatitis with low disease activity: a large pragmatic daily practice study from the BioDay registry.

BACKGROUND: Limited data are available regarding patient-centred dosing of dupilumab for atopic dermatitis (AD) in daily practice. OBJECTIVES: To evaluate our patient-centred dupilumab dosing regimen in daily practice, to assess prognostic factors for successful tapering and to estimate medication-related cost savings. METHODS: This prospective multicentre study included adult patients with AD, participating in the BioDay registry, treated with dupilumab for ≥ 1.3 years. Interval prolongation was considered in the case of dupilumab standard dose for ≥ 1 year and persistent controlled AD [Eczema Area and Severity Index (EASI) ≤ 7; ≥ 6 months]. Primary endpoints were the mean EASI and Numeric Rating Scale (NRS)-pruritus after the start of tapering. Prognostic factors for successful tapering were analysed with logistic regression and a cost-savings analysis was performed. RESULTS: A total of 595 patients were included, of whom 401 patients [mean EASI 2.5 (SD 2.3); NRS-pruritus of 2.4 (SD 1.9) at the start of tapering] prolonged their dupilumab interval. In 83.3% of these patients tapering was successful; most patients used dupilumab every 3 or 4 weeks (Q3W/Q4W). A significant small increase was observed for EASI (highest mean 3.5) and NRS-pruritus (highest mean 3.2) (P < 0.001); however, scores remained low. Predicting successful tapering showed nonsignificant odds ratios for all incorporated variables. The estimated cost savings was €3 977 033.98 for 401 patients between January 2019 and June 2022. CONCLUSIONS: This study showed successful tapering of dupilumab in 83.3% of patients with AD who attempted tapering, while maintaining controlled disease and with the majority using Q3W/Q4W. Interval prolongation can be beneficial both for the patient and from a socio-economic perspective.

Daily Practice Experience of Baricitinib Treatment for Patients with Difficult-to-Treat Atopic Dermatitis: Results from the BioDay Registry.

Clinical trials have shown that baricitinib, an oral selective Janus kinase 1/2 inhibitor, is effective for the treatment of moderate-to-severe atopic dermatitis. However, daily practice data are limited. Therefore, this multicentre prospective study evaluated the effectiveness and safety of 16-weeks' treatment with baricitinib in adult patients with moderate-to-severe atopic dermatitis in daily practice. A total of 51 patients from the BioDay registry treated with baricitinib were included and evaluated at baseline and after 4, 8 and 16 weeks of treatment. Effectiveness was assessed using clinician- and patient-reported outcome measurements. Adverse events and laboratory assessments were evaluated at every visit. At week 16, the probability (95% confidence interval) of achieving Eczema Area and Severity Index ≤ 7 and numerical rating scale pruritus ≤ 4 was 29.4% (13.1-53.5) and 20.5% (8.8-40.9), respectively. No significant difference in effectiveness was found between dupilumab non-responders and responders. Twenty-two (43.2%) patients discontinued baricitinib treatment due to ineffectiveness, adverse events or both (31.4%, 9.8% and 2.0%, respectively). Most frequently reported adverse events were nausea (n = 6, 11.8%), urinary tract infection (n = 5, 9.8%) and herpes simplex infection (n = 4, 7.8%). In conclusion, baricitinib can be an effective treatment option for moderate-to-severe atopic dermatitis, including patients with non-responsiveness on dupilumab. However, effectiveness of baricitinib is heterogeneous, which is reflected by the high discontinuation rate in this difficult-to-treat cohort.

Phototherapy for atopic eczema.

BACKGROUND: Atopic eczema (AE), also known as atopic dermatitis, is a chronic inflammatory skin condition that causes significant burden. Phototherapy is sometimes used to treat AE when topical treatments, such as corticosteroids, are insufficient or poorly tolerated. OBJECTIVES: To assess the effects of phototherapy for treating AE. SEARCH METHODS: We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and ClinicalTrials.gov to January 2021. SELECTION CRITERIA: We included randomised controlled trials in adults or children with any subtype or severity of clinically diagnosed AE. Eligible comparisons were any type of phototherapy versus other forms of phototherapy or any other treatment, including placebo or no treatment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. For key findings, we used RoB 2.0 to assess bias, and GRADE to assess certainty of the evidence. Primary outcomes were physician-assessed signs and patient-reported symptoms. Secondary outcomes were Investigator Global Assessment (IGA), health-related quality of life (HRQoL), safety (measured as withdrawals due to adverse events), and long-term control. MAIN RESULTS: We included 32 trials with 1219 randomised participants, aged 5 to 83 years (mean: 28 years), with an equal number of males and females. Participants were recruited mainly from secondary care dermatology clinics, and study duration was, on average, 13 weeks (range: 10 days to one year). We assessed risk of bias for all key outcomes as having some concerns or high risk, due to missing data, inappropriate analysis, or insufficient information to assess selective reporting. Assessed interventions included: narrowband ultraviolet B (NB-UVB; 13 trials), ultraviolet A1 (UVA1; 6 trials), broadband ultraviolet B (BB-UVB; 5 trials), ultraviolet AB (UVAB; 2 trials), psoralen plus ultraviolet A (PUVA; 2 trials), ultraviolet A (UVA; 1 trial), unspecified ultraviolet B (UVB; 1 trial), full spectrum light (1 trial), Saalmann selective ultraviolet phototherapy (SUP) cabin (1 trial), saltwater bath plus UVB (balneophototherapy; 1 trial), and excimer laser (1 trial). Comparators included placebo, no treatment, another phototherapy, topical treatment, or alternative doses of the same treatment. Results for key comparisons are summarised (for scales, lower scores are better): NB-UVB versus placebo/no treatment There may be a larger reduction in physician-assessed signs with NB-UVB compared to placebo after 12 weeks of treatment (mean difference (MD) -9.4, 95% confidence interval (CI) -3.62 to -15.18; 1 trial, 41 participants; scale: 0 to 90). Two trials reported little difference between NB-UVB and no treatment (37 participants, four to six weeks of treatment); another reported improved signs with NB-UVB versus no treatment (11 participants, nine weeks of treatment). NB-UVB may increase the number of people reporting reduced itch after 12 weeks of treatment compared to placebo (risk ratio (RR) 1.72, 95% CI 1.10 to 2.69; 1 trial, 40 participants). Another trial reported very little difference in itch severity with NB-UVB (25 participants, four weeks of treatment). The number of participants with moderate to greater global improvement may be higher with NB-UVB than placebo after 12 weeks of treatment (RR 2.81, 95% CI 1.10 to 7.17; 1 trial, 41 participants). NB-UVB may not affect rates of withdrawal due to adverse events. No withdrawals were reported in one trial of NB-UVB versus placebo (18 participants, nine weeks of treatment). In two trials of NB-UVB versus no treatment, each reported one withdrawal per group (71 participants, 8 to 12 weeks of treatment). We judged that all reported outcomes were supported with low-certainty evidence, due to risk of bias and imprecision. No trials reported HRQoL. NB-UVB versus UVA1 We judged the evidence for NB-UVB compared to UVA1 to be very low certainty for all outcomes, due to risk of bias and imprecision. There was no evidence of a difference in physician-assessed signs after six weeks (MD -2.00, 95% CI -8.41 to 4.41; 1 trial, 46 participants; scale: 0 to 108), or patient-reported itch after six weeks (MD 0.3, 95% CI -1.07 to 1.67; 1 trial, 46 participants; scale: 0 to 10). Two split-body trials (20 participants, 40 sides) also measured these outcomes, using different scales at seven to eight weeks; they reported lower scores with NB-UVB. One trial reported HRQoL at six weeks (MD 2.9, 95% CI -9.57 to 15.37; 1 trial, 46 participants; scale: 30 to 150). One split-body trial reported no withdrawals due to adverse events over 12 weeks (13 participants). No trials reported IGA. NB-UVB versus PUVA We judged the evidence for NB-UVB compared to PUVA (8-methoxypsoralen in bath plus UVA) to be very low certainty for all reported outcomes, due to risk of bias and imprecision. There was no evidence of a difference in physician-assessed signs after six weeks (64.1% reduction with NB-UVB versus 65.7% reduction with PUVA; 1 trial, 10 participants, 20 sides). There was no evidence of a difference in marked improvement or complete remission after six weeks (odds ratio (OR) 1.00, 95% CI 0.13 to 7.89; 1 trial, 9/10 participants with both treatments). One split-body trial reported no withdrawals due to adverse events in 10 participants over six weeks. The trials did not report patient-reported symptoms or HRQoL. UVA1 versus PUVA There was very low-certainty evidence, due to serious risk of bias and imprecision, that PUVA (oral 5-methoxypsoralen plus UVA) reduced physician-assessed signs more than UVA1 after three weeks (MD 11.3, 95% CI -0.21 to 22.81; 1 trial, 40 participants; scale: 0 to 103). The trial did not report patient-reported symptoms, IGA, HRQoL, or withdrawals due to adverse events. There were no eligible trials for the key comparisons of UVA1 or PUVA compared with no treatment. Adverse events Reported adverse events included low rates of phototoxic reaction, severe irritation, UV burn, bacterial superinfection, disease exacerbation, and eczema herpeticum. AUTHORS' CONCLUSIONS: Compared to placebo or no treatment, NB-UVB may improve physician-rated signs, patient-reported symptoms, and IGA after 12 weeks, without a difference in withdrawal due to adverse events. Evidence for UVA1 compared to NB-UVB or PUVA, and NB-UVB compared to PUVA was very low certainty. More information is needed on the safety and effectiveness of all aspects of phototherapy for treating AE.

Towards personalized treatment in atopic dermatitis.

INTRODUCTION: For many years, oral immunosuppressive drugs such as cyclosporine A, azathioprine, mycophenolic acid, and methotrexate were the only treatment options, in addition to topical treatment, in patients with severe atopic dermatitis (AD). Dupilumab, a monoclonal antibody targeting the IL-4 receptor alpha, is the first antibody-based treatment commercially available for the treatment of AD. In the near future, more antibody-based treatments and small molecules will become available in the treatment of severe AD. AREAS COVERED: This review gives an overview of current and future therapies for severe AD, outlines options to optimize treatment with oral immunosuppressive drugs and gives an insight into the future of personalized treatment in AD. EXPERT OPINION: Due to the heterogeneous character of AD, it is unlikely that all patients will respond equally to these newly tested drugs. We believe that biomarkers will lead to better identification of patients that will benefit from these highly specific, but expensive new treatments. In addition to a role for biomarkers in new treatments, the use of pharmacogenomic biomarkers can improve the efficacy of currently used oral immunosuppressive drugs in AD, which will still be needed for the treatment of moderate to severe AD in the coming years.

Dupilumab in atopic dermatitis: rationale, latest evidence and place in therapy.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. The prevalence of AD is increasing and is currently estimated at 10-20% in adults worldwide. In the majority of patients, AD can be adequately controlled with topical treatment or ultraviolet light therapy, but there is a high unmet need for effective and safe therapeutics in patients with more severe or difficult to treat AD. During the past decade, new advances in the understanding of the underlying immune pathogenesis of AD have led to the development of new, more targeted therapies. Dupilumab, a fully human monoclonal antibody targeting the interleukin (IL)-4 receptor α, thereby blocking the IL-4 and IL-13 pathway, is one of the first biologics that has been developed for AD. Dupilumab has shown promising results in phase III trials and has recently been approved by the US Food and Drug Administration and the European Commission for the treatment of moderate to severe AD. With the approval of dupilumab, we are entering a new era of biological therapeutics in AD management. The place of dupilumab should be established in the current treatment standards. Based on current treatment guidelines and experts' opinions in the management of AD, we have built a proposal for a treatment algorithm for systemic treatment of AD in European countries.

Lymphopenia in atopic dermatitis patients treated with oral immunosuppressive drugs.

INTRODUCTION: Oral immunosuppressive drugs are commonly used in the treatment of atopic dermatitis (AD). In patients with autoimmune- and rheumatic diseases, these drugs have been associated with lymphopenia. Lymphopenia is related to an increased risk of opportunistic infections. The incidence of lymphopenia in patients with AD treated with oral immunosuppressive drugs is yet unknown. OBJECTIVE: To evaluate the occurrence of recurrent lymphopenia in patients with AD treated with oral immunosuppressive drugs and to make recommendations for screening in daily practice. METHODS: Patients with recurrent lymphopenia (i.e. >5 times lymphocyte counts below 0.8 × 109/L) during treatment with oral immunosuppressive drugs were included from our immunosuppressive drugs database and further analyzed. RESULTS: A total of 360 AD patients, treated with oral immunosuppressive drugs, were screened. A recurrent lymphopenia during treatment was found in 11 patients. In 8/11 patients, recurrent lymphopenia was observed during concomitant treatment with prednisone. No serious infections were observed. CONCLUSION: Lymphopenia is occasionally seen in AD patients treat with oral immunosuppressive drugs. Concomitant treatment with prednisone seems to be a risk factor. We suggest to include monitoring of lymphocyte counts in the standard follow-up for all AD patients treated with oral immunosuppressive drugs.

Risk of Non-melanoma Skin Cancer in Patients with Atopic Dermatitis Treated with Oral Immunosuppressive Drugs.

There is uncertainty about the risk of developing non-melanoma skin cancer (NMSC), including basal cell carcinoma and squamous cell carcinoma (SCC), in patients with atopic dermatitis (AD) treated with oral immunosuppressive drugs. A total of 557 patients with AD treated with these drugs in the University Medical Center Utrecht and Groningen, the Netherlands, were analysed. NMSC after oral immunosuppressive treatment was reported in 18 patients (3.2%). The standardized incidence ratio for developing SCC was 13.1 (95% confidence interval (95% CI) 6.5-19.7). Patients developing NMSC were older at the start of therapy (p<0.001) and data lock (p<0.001) compared with patients without NMSC. No significant differences were found in sex, cumulative days of oral immunosuppressive drugs and follow-up between these groups (p=0.42, p=0.88, and p=0.34, respectively). In interpreting these results it is important to include other factors, such as lack of association between treatment duration and tumour development and the long interval between treatment discontinuation and tumour development in some patients.