Dupilumab Treatment of Atopic Dermatitis in Routine Clinical Care: Baseline Characteristics of Patients in the PROLEAD Prospective, Observational Study

Moderate-to-severe atopic dermatitis (AD) is a chronic type 2 inflammatory disease characterised by impaired epidermal barrier, immunological disorders, frequent flares with intense itch, and poor quality of life (QoL) [1‐3]. The reported prevalence of AD in Germany has ranged from 3.7% (n = 1.4 million) [4] to 4.2% [95% confidence interval (CI), 4.1, 4.2%; n = 3.6 million] [5], with an annual prevalence among adults aged > 20 years of 3.3%. Moreover, 31.3% of these adults present with moderate-to-severe AD, without a clear difference between the sexes [5]. A checklist developed to identify patients with moderate-to-severe AD who require systemic treatment is included in the German S2k guideline update, ‘systemic treatment of atopic dermatitis’ [6].

Previously, it was reported that many patients with moderate-to-severe AD experience uncontrolled disease, even after use of intensive topical treatment and/or conventional systemic regimens, such as immunosuppression [7]. This is because some immunosuppressants are only suitable for short-term use because of toxicity (ciclosporin A) or have moderate (azathioprine; off-label in Germany) or unproven (e.g., methotrexate, mycophenolate mofetil, alitretinoin; off-label in Germany) efficacy [6]. As such, disease control, including freedom from itching (often rated by patients as important), is a priority for patients with moderate-to-severe AD [8]. However, it has been reported that patients with AD are undersupplied with treatments, with approximately one-third of patients being treated by a specialist. In addition, innovative treatments, such as dupilumab, are so far rarely prescribed (0.64%) and are primarily prescribed by dermatologists (66.7%) [5].

Dupilumab (Dupixent®) [9], the first biologic licensed for adults and adolescents with moderate-to-severe AD who require systemic therapy, is also licensed in patients aged ≥ 6 years with severe AD [10] and in other type 2 inflammatory diseases [1, 11]. Dupilumab is a fully human monoclonal antibody that blocks the interleukin (IL)-4 and IL-13 signalling pathways, which are key drivers of type 2 inflammation in AD and other type 2 inflammatory diseases, such as severe asthma and chronic rhinosinusitis with nasal polyps [2, 3]. In the pivotal phase III CHRONOS study, dupilumab improved the signs and symptoms of AD compared with placebo, with favourable safety, when added to standard topical corticosteroid (TCS) treatment for 1 year in adults with moderate-to-severe AD [12]. Real-world studies have demonstrated improvements in signs, symptoms and QoL in patients of various age groups that were treated with dupilumab for moderate-to-severe AD. These included two prospective studies conducted in adolescents [13] and adults [14] and a retrospective study in elderly patients (aged ≥ 65 years) [15].

PROLEAD is the largest prospective, non-interventional study in Europe to investigate the effectiveness and safety of dupilumab in adult patients with moderate-to-severe AD in a real-world setting and how patients transition from prior AD treatments to dupilumab in real life. Reported here are baseline characteristics of patients in PROLEAD, reflecting the patients who are usually treated with dupilumab in Germany.

In total, 839 patients were assessed for eligibility, with 828 included in the study; of these, baseline data were available and analysed from 817 patients (Fig. 1) who all received the approved dosage of dupilumab at baseline. Patients were included from 126 study sites throughout Germany with 108 sites being office-based dermatological practices. Approximately half the patients were from large cities (> 100,000 inhabitants; 52.4%); the remainder were from medium- (20,000–100,000 inhabitants; 26.2%) or small-sized (5000–20,000 inhabitants; 15.1%) cities, rural areas (< 5000 inhabitants; 1.6%), or had missing data (4.8%).

The findings of this prospective, non-interventional study describe real-world demographics and characteristics of German patients with AD receiving treatment with dupilumab, using a relatively large sample size for this population. The 126 study sites covered a wide distribution of the use of dupilumab throughout Germany, and there was an equal distribution between sites in large cities compared to sites in medium- and small-sized cities or rural areas. Data on the effectiveness and safety of dupilumab in this patient population will be reported in a future publication. Most patients in PROLEAD had received numerous treatments before initiation of dupilumab but many nevertheless presented with AD-related signs and symptoms as well as impaired QoL. The most common prior topical therapy (within 12 months prior to baseline) was Class 3 TCS and the most common prior systemic treatment was OCS. This reflects the results from the recent German claims-based analysis by Hagenström et al. (2021), which included data from general practitioners, paediatricians, and internists, as well as dermatologists [5]. However, the number of patients receiving topical and/or systemic treatments for AD decreased towards baseline, with approximately half then receiving dupilumab as monotherapy. Moreover, patients receiving dupilumab became less dependent on combination therapy with systemic and topical AD treatment over time. Although combination therapy use reduced with dupilumab, the updated S2k guidelines for systemic treatment recommends that dupilumab is used in combination with a topical anti-inflammatory treatment, as part of a four-step regimen [6]. PROLEAD patients treated with conventional systemic therapies at last prior visit were generally switched to dupilumab without overlap. Although not widely implemented in this study, previous publications have recommended an overlap as practical management for patients transitioning from conventional systemic treatments to dupilumab, as concurrent treatment with these therapies does not alter either drug’s intrinsic risk profile [10]. The proportion of patients with previous and concomitant treatment with antihistamines was unexpectedly high, as there is no evidence for the treatment of pruritus in AD patients and they are not recommended by treatment guidelines. No patients were receiving methotrexate as concomitant medication, potentially as it is not licensed in this indication. Most patients reported that AD either ‘slightly’ or ‘moderately’ hampered their profession/studies/everyday school life; however, a similar proportion of patients reported that AD affects their everyday life in varying degrees, from ‘not at all’/‘does not apply to me’ to ‘quite a bit’/‘very’.

Data from this study indicate that patients in the real-world are less severely affected by AD than those who participated in the pivotal phase III CHRONOS trial in terms of skin lesions at baseline, but not in terms of symptoms or QoL [12]. It should be noted, however, that the CHRONOS study excluded patients who had received TCS or TCIs within 1 week before baseline or immunosuppressive/immunomodulating drugs or phototherapy for AD within 4 weeks before baseline [12]. Interestingly, disease-specific DLQI scores at baseline among the 800/817 patients who completed the questionnaire were higher (mean, 13.9 [7.1]; indicating a large impact on QoL) than those reported for patients with chronic hand eczema included in the German CARPE registry (mean, 8.8, SD 6.3) [18, 19], supporting a high burden of AD in the PROLEAD population. In recent years, PROs have been used in real-world clinical practice as well as in clinical trials and provide an important compliment to clinician-reported outcomes to support decision making [20]. The high baseline DLQI scores are explained by most severe cases of AD receiving dupilumab initially, whereas in later years, physicians would increasingly prescribe dupilumab for moderate AD, following the implementation of dupilumab in routine clinical care. Conversely, the mean (SD) DLQI scores in the present study (13.9 [7.1]) were more similar to those reported in the PsoBest registry (12.4 [3.4]) [21, 22]. Consistently, the physician- and patient-reported severity and burden of AD in PROLEAD were also greater than those reported in the TREATgermany AD registry and prospective, observational, European-wide EUROSTAD study, as indicated by mean respective EASI (22.9 vs. 16.1 vs. 16.2, respectively), SCORAD (63.3 vs. 40.96 vs. not reported), Peak Pruritus NRS (7.4 vs. not reported vs. 5.5), DLQI (13.9 vs. 11.8 vs. 11.8), and POEM (20.4 vs. 16.8 vs. 17.0) scores [23, 24]. Mean IGA scores in PROLEAD (3.3) were comparable to those in EUROSTAD (3.1) [24]. The results of the present and previous studies investigating dupilumab demonstrate the potential to improve management of moderate-to-severe AD.

The rate of co-existing atopic and type 2 inflammatory diseases at baseline was lower in patients included in PROLEAD (51.8%) than in patients treated with dupilumab in CHRONOS (62%) [12]. Additionally, co-existing type 2 inflammatory diseases are most common in patients who receive systemic AD treatment with dupilumab in contrast to other comorbidities, such as rheumatic or metabolic diseases, which are common clinical manifestations in patients with psoriasis [25]. Zander et al. reported that patients with AD in medical history (n = 5883) frequently present with type 2 inflammatory diseases (allergic conjunctivitis: 42.0%; allergic asthma: 17.2%), consistent with the results of PROLEAD (allergic conjunctivitis: 36.8%; bronchial asthma: 22.5%), highlighting the requirement for comprehensive, dermatologically-guided diagnostics in AD to ensure patients receive suitable therapy [26].

Reassuringly, the demographic characteristics of the PROLEAD patient population were consistent with those in the TREATgermany AD registry and AtopicHealth healthcare study of atopic dermatitis in Germany [23, 27, 28]. The TREATgermany registry reported that most patients with AD have an education level of secondary school diploma (37.2%) and are in full-time employment (73.2%), which is comparable to the findings from PROLEAD (Table 1). Comorbidities were also similar between the TREATgermany and PROLEAD patient populations [23].

Interestingly, the most important reason to initiate treatment with dupilumab was that topical therapy alone was insufficient. This attribute has been recently added to step 4 in the four-step therapeutic regimen figure according to AD severity in the updated S2k guideline, “Systemic treatment of atopic dermatitis” for when systemic treatment should be initiated [6]. However, the efficacy and safety of dupilumab presents the potential for inclusion as a possible step 3 option, which describes treatment approaches for moderate eczema. Inclusion of systemic therapy in future guideline updates for treatment of moderate AD might address the unmet need for therapeutic innovations to alleviate the lack of improvement in the quality of care for AD in Germany, as reported by several studies, including AtopicHealth, a national health care study [27‐29].

This guideline publication [6] also lists the checklist to identify patients with moderate-to-severe AD who require systemic treatment. More than 85% of PROLEAD patients fulfil the criteria in all three sections at baseline, with almost all patients fulfilling the sections for relevant objective severity and lack of treatment response. This finding is a reverse validation of the checklist, showing that most patients receiving systemic treatment in this study would have been identified with the checklist as needing such treatment, making it a valuable tool for patient identification.

The results from PROLEAD describe that patients treated with dupilumab present with moderate to severe AD, a median age of 41.0 years, with no difference between sex, and a prevalence of pruritus. The disease burden is further increased in approximately half the patients by the presence of co-existing type 2 inflammatory diseases, notably allergic conjunctivitis and asthma.