Authors: Jeivicaa Thevan, Eloi Schmauch, Jakob Nilsson, Carole Florence Guillet, Andrea Boesch, Lukas Krähenbühl, Barbara Meier-Schiesser, Peter Schmid-Grendelmeier, Thomas Kündig, Antonios G.A. Kolios
Categories: Research Article, Autoimmune blistering diseases, Bullous pemphigoid, Bullous pemphigoid disease area index, Dupilumab, Pruritus
Source: Dermatology (Basel, Switzerland)
Doi: 10.1159/000540590
Dupilumab has emerged as a promising treatment option for bullous pemphigoid (BP). Rapid identification of responders could avoid the need for additional immunosuppressive treatments that are associated with increased morbidity and mortality.
To investigate the course of itch as an early indicator of treatment response, data of 12 BP patients treated with dupilumab at the University Hospital of Zurich were retrospectively evaluated. Disease severity was assessed by bullous pemphigoid disease area index (BPDAI) and pruritus by a numeric rating scale (NRS, 0–10) at baseline; days 1, 3, 14; months 1, 2; and the last follow-up.
A total of 8/12 patients (67%) had complete response, and 4/12 patients (33%) had partial response during dupilumab treatment. Notably, a highly significant reduction of pruritus (p < 0.0001) was observed already on day 1 with further improvement at later time points. Moreover, fast relief of itch could predict treatment response with a significant correlation to clinical response on day 14 (Spearman correlation R 0.70, p value 0.025), with a positive but non-significant trend on day 3 (R 0.63, p value 0.091). Additionally, 92% (11/12 patients) were on dupilumab monotherapy at the last follow-up without any concomitant systemic or topical treatment for BP.
The rapid and significant decline in BP-associated pruritus observed with dupilumab correlated significantly with disease remission. Early evaluation of pruritus response could change how BP is treated in the future and avoid additional immunosuppressive treatment in BP.
Keywords: Bullous pemphigoid, Autoimmune blistering diseases, Dupilumab, Pruritus, Bullous pemphigoid disease area index
Bullous pemphigoid (BP) is the most common autoimmune blistering disease usually affecting elderly patients. BP is associated with significant morbidity and mortality with a mortality rate of up to 20% within the first year of diagnosis [1]. Most systemic treatment options are immunosuppressive, and their excessive usage is considered an important risk factor in causing a fatal outcome [2], implying the need for a more specific immunomodulatory therapy without general immunosuppressive features. In mild to moderate BP after oral systemic steroids, doxycycline is recommended as a systemic therapeutic option. Although not immunosuppressive, doxycycline has only limited clinical efficacy and is considered insufficient to prevent relapses or to avoid the need for systemic steroids, e.g., in only 12% of patients, it was possible to discontinue systemic steroids [3].
A type II inflammatory pattern with the release of cytokines such as interleukin (IL-)4, IL-5, and IL-13 is an important driver in the pathogenesis of BP. Therefore, promising effectiveness of dupilumab, a monoclonal antibody against IL-4Ra, would overcome the issue of general immunosuppression associated with other systemic therapies in elderly patients. More than 250 cases of dupilumab-treated BP have been reported in the literature [4–7] with complete response (CR) rates of 86–92% [8] and a phase 2/3 study to evaluate the efficacy and safety of dupilumab in BP is currently ongoing (LIBERTY-BP, clinical study NCT04206553).
The aim of this study was to investigate the clinical features, in particular the course of itch, of BP patients treated with dupilumab. Our study adds to the current body of literature the fine-meshed assessment of itch and the possibility of using this feature as an early indicator of subsequent treatment response.
A monocentric retrospective cohort study was conducted in the Department of Dermatology at the University Hospital of Zurich between June 2022 and April 2023. All serologically and histologically confirmed BP patients treated with dupilumab during the defined time period were included in this study. Two independent physicians obtained demographics and clinical data by using validated scores, thereby minimizing any potential bias. Disease severity was clinically assessed by bullous pemphigoid disease area index (BPDAI) and pruritus by a worst-itch numeric rating scale (WI-NRS) ranging from 0 to 10, whereas 0 indicated no pruritus and 10 indicated the most severe. The scores were conducted during clinical visits with fine-meshed assessments due to the novelty of this treatment approach and for safety reasons. BPDAI was assessed at the start of treatment (baseline); week 2; months 1, 2; and at the last follow-up. The last follow-up corresponds to the latest clinical evaluation with ongoing dupilumab therapy (Table 1). Pruritus WI-NRS was assessed at start of treatment (baseline); days 1, 3, 14; months 1, 2; and at the last follow-up. We define CR as clinical remission (BPDAI 0) and resolution of itch (0) on any abovementioned time point, whereas partial response (PR) indicates improvement in clinical manifestations and/or pruritus but not full remission.
For statistical comparison between the groups a one-way ANOVA with Tukey’s multiple comparison was performed using the GraphPad Prism and R software. Results with a p value below 0.05 were considered statistically significant.
For correlation analysis and plotting, missing values are ignored. Spearman correlation and associated p value are calculated using the Python SciPy package (scipy.stats.spearmanr). Regression lines are added using Seaborn’s regplot function.
Twelve patients were included in the study (33% female, mean age was 76 ± 15 years) with a mean disease duration of 31.5 ± 19.2 months (Table 1). All patients had serological and histological confirmation of BP diagnosis prior to treatment initiation. Eight patients had moderate (66%, BPDAI ≥20 to <57) and 4 mild (BPDAI <20) BP severity [3]. Prior treatments included topical corticosteroids (TCS) in all patients, doxycycline (n = 10, 83%), azathioprine (n = 5, 42%), and systemic prednisone (PDN, n = 4, 25%). Half of the patients (n = 6) had only received TCS and doxycycline as previous therapy.
Dupilumab was given according to the label in atopic dermatitis starting with 600 mg subcutaneously (s.c.) followed by 300 mg s.c. every 2 weeks. All but 1 patient (11/12 patients, 92%) were without any concomitant systemic treatments on the last follow-up. Also, all but 1 patient (11/12 patients, 92%) had stopped TCS on the last follow-up. Overall, half of the patients (n = 6) did not receive any concomitant systemic therapy during the treatment with dupilumab. Two patients received systemic PDN for 3 and 6 days, respectively, whereas another patient for 9 months and one was on stable 5 mg/d; additionally, 2 patients received doxycycline for 1 and 4 weeks. Concomitant TCS therapy was given for a mean duration of 1 ± 1.4 weeks and 2 patients did not need any TCS. Only 1 patient continued TCS on an intermittent scheme. Patients were on dupilumab for a mean duration of 4.5 ± 3.8 months and all but patient 11 (92%) continued dupilumab treatment at the last visit (Table 1).
CR was seen in 8/12 patients (67%) and PR in 4/12 patients (33%) (Table 2). Mean BPDAI improved significantly from baseline (24 ± 12) versus month 1 (12 ± 15.9), 2 (7 ± 12.3) and the last follow-up (0 ± 6.5) (Fig. 1a, Table 2). Patient 11 with a BPDAI improvement of 50% at week 4 and itch improvement of 90% at day 3 (considered PR), switched treatment due to personal reasons. Importantly, all patients except one (92%) had discontinued all additional systemic and topical treatments at the last follow-up and were maintained on dupilumab monotherapy (Table 1).
Fig. 1. Bullous pemphigoid (BP) severity by bullous pemphigoid disease area index (BPDAI) (a) and mean improvement in pruritus by worst-itch numerical rating scale (WI-NRS) (b) compared to baseline during dupilumab. Baseline to month 1 (p = 0.0433), baseline to month 2, and the last follow-up (p < 0.001). ns, non-significant; (p > 0.05), *p ≤ 0.05, ***p ≤ 0.001, **** = p < 0.0001.
Itch, measured by WI-NRS, improved significantly already by day 1 with a mean reduction of 47.6%, 73.3%, improving further on day 3, 71.2% on day 14, 85.1% on day 28, and 89.1% on day 56, as well as 95.6% upon the last follow-up (all significant p < 0.0001) (Fig. 1b). For individual courses of BPDAI and pruritus see supplementary figures S1-2 (for all online suppl. material, see https://doi.org/10.1159/000540590).
Importantly, pruritus by WI-NRS and BPDAI scores correlated significantly (Fig. 2) across measurements. Even more striking, a comparison of Δ-BPDAI (baseline vs. last follow-up) and Δ-pruritus (baseline vs. either day 3 or 14) was positive but non-significant on day 3 (online suppl. Fig. S3) and significantly positively correlated on day 14 (online suppl. Fig. S4).
Fig. 2. Correlation of BPDAI and pruritus by WI-NRS, across 84 paired measurements (up to 5 time points per patient). Each dot represents a time point where WI-NRS and BPDAI are both measured, for 1 patient and one time point (data separated by patient shown on online suppl. Fig. S2). Spearman correlation 0.54, associated p 7.22e−05.
In some patients, intermittent values were missing or could not be reconstructed retrospectively (Table 2). No significant difference in the course of itch was seen in CR versus PR from day 1 to month 1 (online suppl. Fig. S5) and no clinically significant side effects were reported. Additionally, dissecting the course of itch and treatment response in patients with mild versus moderate disease revealed positive and significant correlation across measurements in both groups (online suppl. Fig. S6).
Blood samples were not obtained consequently in patients as it is not generally required during dupilumab therapy. In 8 patients differential blood count was taken sequentially but not consequently at all follow-ups. Three patients showed elevated eosinophil counts up to 1.7 G/L at baseline which normalized within 2 weeks. The other 5 patients had normal eosinophil counts. In patients where serum immunoglobulin E (IgE) was measured (n = 9), it did not change with treatment. BP autoantibodies against hemidesmosomes BP180 and BP230 were sequentially analyzed in the majority of the patients (9 of 12, 75%). Two patients had a significant reduction in anti-BP180, two had an increase, whereas in the others (n = 5) anti-BP180 as well as in general anti-BP230 values remained stable (Table 1).
Several noteworthy clinical features are summarized in the following paragraphs. Patient 2 received adjuvant pembrolizumab due to metastatic malignant melanoma but was already in follow-up at BP disease onset. The BP was considered immunotherapy-associated. Currently, the patient is on tapering of dupilumab to every 3rd week without relapse of his BP. Patient 6 has a concomitant psoriasis. Several attempts to treat both diseases with a monotherapy had failed. The psoriasis is treated with risankizumab and the patient is in complete remission for both diseases. Patient 9 also suffered from atopic rhinitis with anosmia, middle ear involvement and cough. She improved dramatically after starting dupilumab with reconstitution of smell, blocked nose, hearing, and cough, in addition to the improvement of her BP. Patient 10 suffers from concomitant atopic dermatitis, which also improved during treatment.
Patient 12, with a histological (H and E as well as direct immunofluorescence) and serologically confirmed diagnosis of BP upon referral, was already on dupilumab when later developed features of epidermolysis bullosa acquisita (EBA) by developing also antibodies against collagen VII and a floor pattern in salt split technique, coinciding with EBA, which we interpreted as an overlap of BP and EBA as in both serology and histology findings of both diseases were present. Systemic steroids were necessary in addition to dupilumab. After tapering systemic steroids, the patient had a mild flare of her EBA. We used a single dose-increase (“re-introduction”) of dupilumab with 600 mg once at month 6 and the patient came into full remission. Systemic PDN could be stopped completely at month 9 and the patient has maintained CR since then.
More than 250 cases of dupilumab-treated BP have been reported with CR rates of 86–92%. Our data show CR versus PR rates of 67 versus 33%, respectively (Table 1). Here, we add our observation that pruritus, measured by WI-NRS, decreases very quickly and significantly already by day 1 (Fig. 1) with a mean reduction of 47.6% (p < 0.0001), 73.3% on day 3, up to 95.6% on the last follow-up (all significant p < 0.0001) (Table 2), which is strongly associated with disease remission measured by BPDAI (Fig. 1). More importantly, early and fast reduction of itch correlates significantly with disease improvement, which could potentially be used as a predictor of treatment response (online suppl. Fig. S4). Although pruritus reduction is a known effect on BP patients after dupilumab treatment, the rapidity of this pruritus reduction combined with the predicted disease remission is crucial to identify patients with a good treatment response already at an early stage. The advantage of pruritus assessment versus other clinical or dermatological signs of the disease is that pruritus can be evaluated easily much earlier on a daily basis. We did not see a statistically significant correlation on day 1 or day 3, but a significant correlation could be observed on day 14. Due to the low number of patients, larger future studies evaluating itch in the early course of dupilumab therapy are needed to evaluate the optimal time point of pruritus assessment.
The effectiveness of a treatment is not only characterized by the amelioration of objective scores such as BPDAI but also by subjectively assessed pruritus development. Current literature suggests that most of the effective treatment options for BP improve BPDAI as well as pruritus though this relation is not clearly evaluated so far. Therefore, the shown correlation between BPDAI with WI-NRS for dupilumab can also be presumed for other BP treatments.
Phase 3 studies of dupilumab for other indications like atopic dermatitis and prurigo nodularis report a significant reduction of itch at day 2 (in around 50% of patients) or week 12 (improvement of ≥4-point in 44% of patients), respectively [9, 10]. In the PRIME and PRIME 2 studies in prurigo nodularis, WI-NRS start to differ significantly from week 3–4 compared to placebo. Our data suggest that the assessment of itch could be an early indicator of treatment response in dupilumab-treated BP and could help treatment decisions with regard to the likelihood of subsequent response.
Notably, patients with an already established adjunctive treatment with corticosteroids did not report any itch improvement until beginning with dupilumab. This emphasizes that the observed rapid pruritus reduction after dupilumab application is merely attributed to the effects of dupilumab. Additionally, we could show that not only itch is reduced significantly by day 1 (Fig. 1) but also concomitant systemic corticosteroids (n = 11/12, patient 6 ongoing) and TCS (n = 11/12, patient 11 ongoing) could be discontinued rapidly (Table 1).
The underlying molecular mechanisms of pruritus in BP are not clear yet but involve among other components, eosinophils and basophils, several cytokines such as IL-4/−13/−31 and IgG/E autoantibodies [11]. Eosinophils seem to play a major role in the pathogenesis of pruritus in BP as they are elevated in the skin lesions of BP [12, 13]. Particularly, they are a central source of IL-31 that is related to pruritus severity by inducing the secretion of itch mediators such as brain natriuretic peptide and causing nerve growth. Besides, IL-31 is increased in lesional skin and serum of BP patients and correlates with eosinophilia and anti-BP180 IgE antibodies. Also, the IL-31 receptor OSMRβ is related to the itch intensity of BP. IgE autoantibodies in turn (anti-BP180 but not anti-BP230 antibodies) are related to BP intensity. Moreover, T cells and basophils producing IL-4 and IL-13 are elevated in BP. Especially, IL-13, that correlates with pruritus intensity, is known to recruit eosinophils, and is assumed to be important in itch development, e.g., by intensifying pruritogenic sensory neurons. Additionally, the recruitment of eosinophils is also induced by periostin and basophils. Basophils also produce IL-31, IL-13, IL-4, and histamine, and are related to pruritus severity in BP [11]. Although IL-31 plays a major role in pruritus induction in several inflammatory skin diseases [13], and its concentration was higher in BP lesions, an association between IL-31 concentration and itch intensity could not be established [14]. In atopic dermatitis, IL-31 was not reduced during dupilumab treatment [15]. Interestingly, a recent case report revealed a newly developed BP after the application of an anti-IL-31 receptor antibody, nemolizumab, in a patient with atopic dermatitis [16] and a remission of BP after finally being treated with dupilumab. Dupilumab modulates the IL-4/IL-13 signaling pathway and some studies further reported reduced eosinophil counts whereas others did not [15, 17, 18], whereby a direct inhibition of IL-31 may not reduce eosinophilia and may lead to a compensatory increase of other interleukins. This suggests that the modulation of IL-4/-13 may have a higher or earlier effect in the inflammatory and pruritogenic cascade of BP.
Understanding the interaction and role of the itch mediators may enable a combined targeted treatment approach for BP in the future, where the biologic agents could complement each other and increase the effect of dupilumab on pruritus. Limitations of the study are its retrospective character and small sample size. Larger cohorts including the ongoing phase 2/3 study with dupilumab in BP are necessary to identify if early pruritus reduction can be used as an indicator of treatment responders.
Taken together, dupilumab adds to the existing treatment options for BP as a safe treatment without strong general immunosuppressive action. Patients with BP bear the risk of increased mortality by the combination of risk factors such as extensive disease with open wounds, advanced age, and the use of systemic immunosuppression. In this specific disease, a treatment without strong general immunosuppressive effects such as dupilumab with reported CR rates of over 90% would be preferred. Our data indicates that early pruritus reduction could be extrapolated in the way that a single injection of 600 mg dupilumab could be used to identify potential responders where other systemic therapies could be withheld. This could change how BP is treated in the future, esp. in patients with an augmented risk of increased mortality in the setting of advanced age and significant comorbidities. Our data not only indicate this quick reduction in pruritus but also the possibility to stop early concomitant systemic corticosteroids and TCS. Larger studies are needed to confirm our promising observations.
This study was approved by the Cantonal Ethic Commission of Zurich and the Institutional Review Board (KEK 2019-00153). Written informed consent was given by each patient.
The authors have no conflicts of interest to declare.
This research was supported by the Department of Dermatology, University Hospital Zurich and Bruno Bloch Foundation (to A.G.A.K.).
Conceptualization: A.G.A.K.; data acquisition and A.G.A.K., T.K., P.S.-G., J.N., C.F.G., A.B., L.K., B.M.-S., and J.T.; methodology and writing‐original J.T., E.S., and A.G.A.K.; and writing‐review and all authors.
This research was supported by the Department of Dermatology, University Hospital Zurich and Bruno Bloch Foundation (to A.G.A.K.).
The data that support the findings of this study are not publicly available as they contain information that could compromise the privacy of research participants but are available from the corresponding author (A.G.A.K.) upon reasonable request.
The data that support the findings of this study are not publicly available as they contain information that could compromise the privacy of research participants but are available from the corresponding author (A.G.A.K.) upon reasonable request.