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Pharmacological advances in pemphigoid
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ScienceDirect Pharmacological advances in pemphigoid Roberto Maglie1,2 and Michael Hertl1 Pemphigoid is the most common autoimmune blistering disease. IgG and IgE autoantibodies against the hemidesmosomal antigens Bullous Pemphigoid (BP) 180 and BP230 are of pathogenic relevance, since autoantibody– antigen binding results in complement activation, immune cells infiltration, impaired hemidesmosomal function, and loss of dermal–epidermal adhesion. Systemic steroids and immunosuppressants are frontline therapies in pemphigoid, but result in substantial morbidity and increased mortality. A large randomized multicenter study highlighted doxycycline as a feasible alternative to systemic corticosteroids in patients not suitable for long-term steroid use. In recent years, new targeted therapies, including intravenous immunoglobulin (IvIg), rituximab, omalizumab, and immunoadsorption, have proven efficacy in the refractory setting, but, with the exception of IVIG, large randomized trial has not been performed yet. Basic research studies have now shed light on the pathogenic role of eosinophils and autoreactive T-helper 2 cells in pemphigoid, inducing tissue damage and sustaining autoantibody production by autoreactive B-cells, respectively. Indeed, eosinophils and Th2-related cytokines have become attractive therapeutic options. Moreover, Interleukin-17 related inflammatory pathways have been also shown to participate in the blistering process. This review discusses current evidence for the use of targeted therapies in pemphigoid as well as most relevant pharmacologic advances and new drugs currently under clinical investigation. Addresses 1 Department of Dermatology, Philipps University, Baldingerstr., Marburg, Germany 2 Department of Surgical and Translational Medicine, Section of Dermatology, University of Florence, Florence, Italy Corresponding authors: Maglie, Roberto ([email protected]), Hertl, Michael ([email protected])
Current Opinion in Pharmacology 2019, 46:34–43 This review comes from a themed issue on Dermatology Edited by Sonja Sta¨nder and Mette Deleuran
https://doi.org/10.1016/j.coph.2018.12.007 1471-4892/ã 2018 Elsevier Ltd. All rights reserved.
Introduction Pemphigoid, or bullous pemphigoid (BP) or cutaneous pemphigoid, represents the most common autoimmune Current Opinion in Pharmacology 2019, 46:34–43
blistering dermatoses. It is a B-cell driven disease: selfreactive B-cells produce autoantibodies, mainly of the IgG subclass, against BP180 and BP230, proteins responsible for the adhesion of basal keratinocytes to the basement membrane zone (BMZ). Binding of IgG autoantibodies to BP180, and specifically to the BP180-NC16A subdomain, activates distinct inflammatory pathways, that is, complement activation, mast cell degranulation, release of pro-inflammatory cytokines and chemokines and recruitment of neutrophil and eosinophil granulocytes, and promotes the internalization and degradation of BP180 [1,2]. This leads to dermal–epidermal separation, which clinically corresponds to the appearance of skin blisters. In addition to BP180 NC16A IgG antibodies, BP patients may subsequently develop autoantibodies against other epitopes of both BP180 and BP230, a phenomenon referred to as epitope spreading, which has been demonstrated to correlate with the severity of BP in disease course [3–5]. Recently, specific IgE targeting the NC16A domain of BP180 has been identified and has been shown to play a supportive role in the pathogenesis of BP, mainly by triggering mast cell and eosinophil degranulation [5]. Specific serum IgE concentrations parallel disease activity, making them an attractive therapeutic target [6]. BP predominately affects the elderly (peak at 60– 80 years). Its annual incidence varies from 2.4 to 21.7 new cases per million population worldwide [7,8]. Noteworthy, the incidence of BP is increasing, possibly due to the association of BP with certain internal diseases, including neurologic disorders, diabetes mellitus, and malignancies [7,9]. Drugs are also a known trigger of BP. Two large case–control studies reported a statistically significant association of BP and chronic use of several drugs, with special regard to diuretics, including spironolactone and loop diuretics [10,11]. Other studies have recently confirmed the increased risk of developing BP among diabetic patients using dipeptidyl peptidase IV inhibitors, mostly vildagliptin and linagliptin [12]. Of note is also the increasing number of reports addressing BP as an emerging side effect of anticancer therapies including immune checkpoint inhibitors targeting programmed cell death (PD) 1 and PD ligand-1 [13]. Typically, BP manifests with tense blisters, arising from erythematous-urticarial plaques or non-inflamed skin (Figure 1). Atypical presentations, referred to as ‘nonbullous pemphigoid’, include erythematous patches, urticarial plaques, papules, nodules, excoriations, eczema, and erythroderma (Figure 1). Pruritus is always present and may occur as a prodromal symptom [1,14], thus www.sciencedirect.com
Emerging therapies in pemphigoid Maglie and Hertl 35
Figure 1
(c)
(a)
(b)
(d) Current Opinion in Pharmacology
(a) and (b): Different clinical manifestations of pemphigoid: (a) tense blisters arising on erythematous inflamed skin; (b) papules with crusts and excoriations due to intense itching; (c), (d) immunopathologic findings of pemphigoid: (c) direct immunofluorescence of perilesional skin reveals linear deposition of IgG and C3 at the basement membrane zone (BMZ); rarely linear IgE deposition could be also detected; (d) indirect immunofluorescence detects circulating anti BMZ IgG antibodies; on salt split skin, IgG antibodies are detected on the epidermal side of the BMZ.
highlighting the concept that BP should be suspected in patients, especially elderly, complaining of pruritus with normal appearing skin. As per expert consensus recommendation, the presence of pruritus is sufficient for establishing the diagnosis of BP, if specific immunopathologic criteria are fulfilled [15]. It is, however, remarkable that IgG reactivity against BP180 and BP230 as well as IgE reactivity against BP180 may be found in a small percentage of elderly patients with non BP pruritic dermatosis, thereby raising speculation on the existence of a pre-clinical disease stage [16,17]. Making the diagnosis of BP relies on the combination of clinical, histopathological, and immunopathological findings. Direct immunofluorescence (DIF) is the most sensitive and specific diagnostic tool, showing linear deposits of IgG and the C3 complement fraction along the BMZ (Figure 1). Assessing serum concentrations of circulating autoantibodies by means of Enzyme Linked Immunosorbent Assay (ELISA) not only is of diagnostic significance, but also serves as a tool for monitoring the disease status and response to treatment, since circulating IgG autoantibodies, and particularly anti-BP180 IgG, parallel both disease activity and severity, and correlate with the risk of mortality [1,4]. The pathogenic meaning of anti-BP230 autoantibodies is, however, controversial. Studies have shown the lack of correlation between such autoantibodies and clinical scores including the Bullous Pemphigoid Disease Area and Activity Index (BPDAI) and Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) [18,19]. In contrast, a minority of BP patients only present with antiBP230 serum IgG. In these patients, there is a weaker www.sciencedirect.com
deposition of IgG1, IgG3, and complement in the skin, whereas circulating autoantibodies are mainly of the IgG4 subclasses, explaining the milder clinical course compared to anti-BP180 IgG or anti-BP180/BP230 IgG type BP [20]. On the contrary, p-200 pemphigoid is a rare variant of the pemphigoids, where laminin-g-1 functions as the main antigenic target. These cases feature overlapping clinical and immunopathologic characteristics of BP and epidermolysis bullosa acquisita but show a more favorable clinical course like in classic BP [21]. Treating BP is largely based on immunosuppressants. Still, systemic glucocorticoids represent the mainstay of therapy [22]. In 2002, a randomized trial by Joly et al. demonstrated that applying superpotent topical steroids was as effective and safe as oral prednisone in patients with moderate BP and even superior and safer in patients with severe disease [23]. However, adherence to treatment can be quite challenging. Immunosuppressants (i.e. azathioprine, methotrexate, ciclosporin, mycophenolate mofetil) or immunomodulators (i.e. dapsone) are usually given in addition to oral glucocorticoids due to their steroid-sparing effect [22]. In light of a lack of large randomized trials, there is no clear-cut evidence to prefer one of these agents instead of another. A recent German multicenter prospective randomized trial compared the steroid-sparing effects of azathioprine and dapsone: both drugs were associated with a reduced one-year mortality and showed no differences in terms of safety; however, dapsone demonstrated a greater steroid sparing effect [24]. Current Opinion in Pharmacology 2019, 46:34–43
36 Dermatology
Long-term immunosuppression leads to major side effects, mostly infections, which partly account for the higher mortality seen in BP patients compared to the general population [25]. Indeed, there is an urgent need for developing new treatment strategies aimed at targeting-specific pathogenic disease pathways and, at the same time, with a more favorable safety profile in this high-risk patient population. This review indeed focuses on the main pharmacologic advances, from the use of tetracyclines as a first line treatment to newly developed targeted therapies, which are gaining major clinical application in the management of BP.
Doxycycline as a first line therapy in pemphigoid Doxycycline, a semisynthetic second generation tetracycline, is a bacteriostatic agent that inhibits bacterial protein synthesis by targeting the 30S subunit of bacterial ribosomes, and is active against a broad spectrum of grampositive and gram-negative bacteria. In addition, doxycycline, as well as other tetracyclines, exerts a plethora of anti-inflammatory effects, explaining its efficacy in inflammatory diseases of the skin, such as acne vulgaris [26]. Doxycycline has been shown to inhibit the activation of metalloproteinases, decrease leukocytes chemotaxis and down regulate many pro-inflammatory cytokines, including TNF-alfa, IL-6 and IL-8, which are all involved in blister formation in BP [26]. Because of its anti-microbial, anti-inflammatory and possibly neuroprotective properties [27], doxycycline has been considered as an attractive therapeutic strategy in BP. Several studies indicated rapid clearing of skin blisters along with a generally good safety profile using doxycyclines, or other tetracyclines, either alone or in combination with nicotinamide [28,29,30]. Most of them, however, lacked a randomized design and were limited by the small number of enrolled patients. In 2017, Williams et al. published the results of a large, multicenter, parallelgroup randomized, non-inferiority trial (the BLISTER study) comparing doxycycline 200 mg/day and oral prednisolone 0.5 mg/kg/day in patients with newly diagnosed BP. The study indicated that doxycycline was not inferior (assuming a predefined non-inferiority margin of 37%) to prednisolone in achieving disease control at 6 weeks, but safer in terms of rate of serious adverse events and treatment-related death over a 56-week period [30]. One year later, the same authors published the costeffectiveness analysis of the trial, showing that doxycycline had comparable costs and quality of life improvement as prednisolone in patients with low-to-moderate BP, whereas prednisolone resulted in a higher quality of life improvement and reduced costs in patients with severe BP [31]. The results of the BLISTER study have been a matter of major controversies. Some authors noted that the statistical design might have biased the results in favor of doxycycline. Controversial issues include: i) the generous predefined non-inferiority Current Opinion in Pharmacology 2019, 46:34–43
margin, ii) the fact that patients were allowed to use topical steroids, iii) the end-point for effectiveness assumed as three blisters or fewer instead of skin lesions clearance, and iv) the initial fixed 0.5 mg/kg/day prednisolone dose regardless of disease severity for patients randomized into the prednisolone group [32]. Although the data are still not convincing to prefer doxycycline over glucocorticoids as a first line therapy in BP, the BLISTER study has strengthened the potential usefulness of doxycycline, maybe combined with high potency topical steroids, in naı¨ve patients with low disease activity or with comorbidities limiting the use of systemic glucocorticoids. Moreover, doxycycline has emerged as a conceivable maintenance following an initial steroid tapering course, as a tool to reduce the cumulative steroid dose and the use of adjuvant immunosuppressants. However unmet concerns about long-term doxycycline use include the emergence of bacterial resistance as well as a possible enhanced risk of non-melanoma skin cancer (NMSC), conceivably related to the drug-induced phototoxycity [26,33].
Targeted therapies in pemphigoid Currently available targeted therapies are indicated as a therapeutic option for BP patients resistant to oral glucocorticoids and immunosuppressants. They include: intravenous immunoglobulins (IvIg), the anti CD20 monoclonal antibody, rituximab, immunoadsorption (IA) and the anti-IgE monoclonal antibody, omalizumab [22,34]. IvIg are a highly effective therapy in BP. IvIg have pleiotropic anti-inflammatory effects [34], yet their mode of action in BP remains only partly understood. IvIg may induce saturation of the FcRn receptor, thereby reducing pathogenic serum autoantibodies [35]. In cultured keratinocytes, IvIg were shown to prevent BP180 depletion induced by pathogenic antibodies through anti-idiotypic antibodies that inhibit autoantibody binding to BP180 [36]. Sasaoka et al. recently showed that IvIg induce reduction of circulating pathogenic antibodies, amelioration of skin fragility and disease severity in a dose-dependent manner both in the passive-transfer and active mouse BP model [37]. They also showed that IvIg downregulated the serum level of inflammatory cytokines and chemokines and reduced keratinocyte secretion of IL-6 both in vitro and in vivo [37]. Indeed several case reports and studies reported meaningful clinical response of severe/refractory BP following IvIg treatment [34,38,39]. Further, their clinical efficacy has been recently demonstrated in a randomized, placebo-controlled, double blind trial. Remarkably, no significant reduction of anti BP180 antibodies was observed between the IvIg group compared to placebo [40]. Rituximab, an anti CD20 chimeric IgG1 monoclonal antibody, has been also successfully tried in patients with www.sciencedirect.com
Emerging therapies in pemphigoid Maglie and Hertl 37
recalcitrant BP [41–43]. Although no randomized placebo controlled studies have been yet conducted in BP, rituximab seems to be less effective in BP compared to pemphigus [44]. Response to treatment is also delayed (about four months, compared to two months for pemphigus) [44], thus suggesting that depletion of self-reactive B-cells and decrease of circulating anti-BP180 antibodies may not impair other critical pathogenic pathways of the disease. Nevertheless, first line rituximab treatment resulted in reduced one-year mortality compared with standard glucocorticoid therapy alone in one retrospective study [45], providing support for a more beneficial application of rituximab in the untreated disease than in the recalcitrant one. Further, combining rituximab with IvIg or immunoadsorption (IA) also demonstrated efficacy [46,47,48]. IA treatment relies on the selective removal of IgG antibodies from the plasma. Besides lowering serum concentrations of pathogenic IgG autoantibodies, IA likely causes their redistribution from the skin to the systemic circulation, preventing IgG binding to the cognate skin antigen. IA is an expensive treatment; side effects, including bacterial sepsis secondary to catheter infections, are also relevant [34]. However, IA has been shown to be of clinical benefit in patients with high disease activity and elevated serum autoantibodies levels. Two studies reported sustained remission using IA in combination with oral and topical glucocorticoids and dapsone in patients with untreated or recalcitrant BP. The reportedly prolonged decrease of anti BP180 autoantibodies following IA suggests that passive removal of circulating autoantibodies may downregulate their production through a yet unexplained mechanism. [48,49]. Several experimental studies support targeting IgE in BP. IgE binding to BP180 NC16A was shown to reduce the formation of hemidesmosomes via keratinocyte production of IL-6 and IL-8 [34]. Both mast cells and eosinophils express the high affinity IgE receptor, FceRI, and are activated by anti BP180 IgE/FceRI binding [50]. In a study by Lin et al. injection of anti BP180 NC16A IgE into mice expressing both human NC16A and FceRI resulted in skin eosinophil infiltration and blistering, whereas injection into NC16A/FceRI knockout mice did not [5]. However, despite positive clinical outcome reported in some case reports and series [6,34,51–53,54,55], the long-term efficacy of omalizumab in BP remains far less clear, since disease relapse seems to occur shortly following drug discontinuation [56]. Furthermore, identifying the ideal candidate for anti IgE directed therapy might be challenging. Accordingly, assessing serum titer of anti BP180 IgE by ELISA is not routinely available. Conversely studies aimed at correlating anti BP180 IgE with specific clinical phenotypes, that is presence of urticarial plaques, have yielded contrasting results [57]. www.sciencedirect.com
Although omalizumab may be considered as an option for patients with refractory disease, it is advisable to inform patients about its off-label use and the lack of evidence clearly supporting its efficacy and safety in BP. As a result, it may be considered after failure or in presence of contraindications to other third line therapies such as IvIg or rituximab; dosing total and specific IgE serum concentration can be recommended before treatment, although a direct link with treatment success has yet to be proven. Summary of the main relevant studies concerning targeted therapies currently in use for refractory BP are listed in Table 1.
Future therapeutic perspectives The association of BP with certain human leukocyte antigen (HLA) alleles, such as DQB1*03:01, which correspond to MHC-class II molecules, points to the involvement of autoreactive T helper cells in the pathogenesis of BP [58–60]. Accordingly, both IgG autoantibodies and Th cells from patients with BP were shown to recognize identical or similar epitopes of BP180 and even healthy individuals carrying BP predisposing alleles may show a peripheral T-cell response against BP180 [59–61]. However, in contrast to predisposed healthy individuals, BP patients show a predominant Th2-type response, suggesting that Th2 cells are primary involved in the loss of tolerance against BP180. Likewise, Th2-related cytokines, including IL-4 and IL-5, and chemokines, including eotaxin and monocyte chemoattractant protein 4 (MCP-4, also called CCL-13), are over represented in lesional BP skin, especially in the early phase of the disease [62,63]. Autoreactive Th2 cells are thought to exert a dual role in BP: they stimulate proliferation and autoantibody production by B-cells via CD40–CD40L interaction and contribute to eosinophil recruitment and activation. Eosinophil degranulation results in dermal– epidermal separation but also stimulates both Th cell polarization and Th2 cell recruitment via a paracrine feedback loop [63,64]. IL4, IL5, which are produced by Th2 cells and eosinophils, and eotaxin which is produced by both eosinophil and keratinocytes, are among the key regulators of the eosinophil-Th2 cell cross-talk in BP [64]; interestingly, a phase II study (NCT02226146) on the efficacy and safety of bertilimumab, a human monoclonal antibody targeting eotxain-1 has recently been completed. The results demonstrated an 81% reduction in disease severity, along with a significant steroid-sparing effect after only three bertilimumab infusions. The drug was well tolerated and no significant adverse event was reported [65]. Likewise, mepolizumab, an IL-5 inhibitor, is also under clinical evaluation in a phase II trial (NCT01705795). Conversely, Kaybe et al. have recently reported on the clinical efficacy of dupilumab, a monoclonal antibody Current Opinion in Pharmacology 2019, 46:34–43
38 Dermatology
Table 1 Summary of the main relevant studies, excluding case reports, on currently available targeted therapies indicated for the management of pemphigoid First author/year of publication
Study design
Number of Treatment schedule/dose patients
Intravenous immunoglobulin Ahmed, 2001 [39] Retrospective
15
Ahmed, 2016 [46]
12
Retrospective
Amagai, 2017 [40] Multicenter, randomized, placebo-controlled, double-blind Rituximab Lourari, 2011 [42]
56
IvIg 2 g/kg/cycle at 4-week intervals until clinical response and then at 6–8–10–12– 14–16 week intervals
Sustained clinical remission achieved in all cases, enabling successful steroid tapering. No significant adverse events were recorded. Clinical remission paralleled decreasing autoantibody concentrations. Phase 1: one IvIg cycle followed by Complete remission achieved in all patients. 8 weekly infusions of rituximab and then Relapse occurred in 2/10 patients. Re4 other rituximab infusions once a month; treatment with RTX led to complete remission phase 2: IvIg at monthly intervals; phase 3: in these patients. No serious adverse events IvIg at 6–8–10–12–14–16 week intervals recorded. 400 mg/kg/day for 5days (2 g/kg/cycle) Greater reduction of disease activity score at 15 days and through the observation period. Statistically significant reduction of DAS for severe cases (DAS 40). No serious adverse events recorded.
Retrospective (including patients with BP and MMP)
7
4 weekly i.v. infusions of 500 mg
Hall 3rd, 2013 [41]
Prospective
7
1000 mg i.v. at days 0 and 14
Cho, 2015 [45]
Retrospective (rituximab plus prednisone vs prednisone alone)
32
4 weekly infusions of 500 mg
28
500 mg or 1000 mg at days 0 and 14, followed by 500 mg at 6–12–18 months.
Immunoadsorption Kasperkiewiez, Open label pilot 2014 [48]
7
Protein A IA combined with oral prednisolone and dapsone
Hu¨bner, 2018 [49]
Case series
20
Protein A IA combined with oral prednisolone, dapsone and topical clobetasol
Omalizumab Yu, 2014 [55]
Open, non controlled 6
Lambert, 2018 [44] Retrospective (including patients with BP, MMP, EBA and DIGAL)
Balakirski, 2016 [54]
Case series
2
Synopsis
Among 4 patients with BP, two reported a complete response, one a partial response and one died 10 days following the first rituximab infusion. Clinical remission achieved in all cases enabling successful tapering of prednisone. Only 2 patients relapsed. Lower BAFF serum levels were associated with disease relapse. No serious adverse events recorded. Complete remission achieved in 90% of patients in the rituximab group. Patients in the rituximab group showed a slightly lower rate of infections and reduced 1-year mortality compared to the prednisone group. Rituximab at 1000 mg at days 0 and 14 was shown to be higher effective than at 500 mg. Among the BP included patients (n = 8), disease control was achieved in 83.3%, partial remission in 62.5%, and complete remission in 12.5%; 71.4% of patients relapsed. BP patients showed a poorer response (albeit not statistically significant) compared to MMP patients. One BP patient died due to bacterial sepsis. All patients achieved complete remission 1–3 months after IA; 6 of 7 patients showed longterm complete remission. 42% and 68% of patients were in complete remission at the 1-month and the last followup visit respectively; adverse events occurred in 65% of patients.
300 mg or 375 mg sc; dose intervals range: Significant improvement of disease activity, 2–8 weeks cessation of new blisters, amelioration of pruritus and decrease of immunosuppressants in 5 of 6 patients. No adverse events recorded 300 mg sc every 3 or 4 weeks Significant improvement of disease activity and cessation of pruritus was observed in both cases, enabling successful prednisone tapering. No adverse events recorded.
Abbreviations: IvIg, intravenous immunoglobulin; BP, bullous pemphigoid; BAFF, B-cell activating factor; MMP, mucous membrane pemphigoid; EBA, epidermolysis bullosa acquisita; LABD, linear IgA dermatosis; IA, immunoadsorption.
Current Opinion in Pharmacology 2019, 46:34–43
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Emerging therapies in pemphigoid Maglie and Hertl 39
Table 2 Summary of the main monoclonal antibodies, which represent future therapeutic perspective in pemphigoid Drug name
Class
Molecular target
Type of study/clinicaltrial.gov identifier
Bertilimumab
Human monoclonal antibody
Eotaxin-1
Mepolizumab
Human monoclonal antibody
IL-5
Dupilumab
Human monoclonal antibody
Ixekizumab
Human monoclonal antibody
IL-4 receptor subunit a IL17A
Sutilmimab
Human monoclonal antibody
C1s
Interventional, open label, phase 2; completed; NCT02226146. Results showed a 84% reduction of disease activity with a steroid sparing effect following 3 drug infusions. Interventional randomized, placebo-controlled, double-blind, phase 2; completed; NCT01705795 No clinical trials currently ongoing; efficacy reported in one case report [66]. Interventional, open-label, single-arm phase 2 study; recruiting; NCT03099538. No studies on BP currently ongoing; safety assessed in a phase I, first-in-human, double-blind, randomized, placebo-controlled study (NCT02502903).
Abbreviations: IL, Interleukin; C1s, C1s complement fraction.
against IL-4 and IL-13, in a case of refractory BP [66] (Table 2). Recent evidence also suggests the involvement of IL-17 in the pro-inflammatory amplication process in BP. IL-17 is elevated in the blister fluid and perilesional skin of BP patients and is produced by both lymphocytes and innate immune cells, including neutrophils and mast cells, under the influx of IL-6 and IL-23 [67,68]. IL-17 activates both human neutrophil elastase and MMP-9, which are crucial for the blister formation [67]. Accordingly, inhibition of IL-17A was shown to prevent dermal–epidermal splitting in cryosections of normal human skin incubated with anti-BP180 IgG and leukocytes. Serum IL-17A levels were also shown to correlate with disease severity in the passive transfer mouse model, suggesting that targeting IL-17 and its related pathways might be a therapeutic strategy in BP [68]. A clinical trial evaluating the efficacy of ixekizumab, a high-affinity fully human monoclonal antibody targeting IL17A, in patients with untreated and recalcitrant BP is currently ongoing (Table 2). IL-23 is the main molecule promoting over expression of IL-17. IL-23 was shown to be highly present in the blister fluid of BP patients [67]. A recent study by Ple´e et al. demonstrated that both IL-17 and IL-23 serum levels were elevated at the baseline in BP patients who experienced a relapse after initial disease control. Further, they postulated that IL-23 could also co-operate in BP pathogenesis independently from IL-17 and via induction of MMP-9 secretion by macrophages and dendritic cells [69]. Interestingly, ustekinumab, an inhibitor of IL-12 and IL-23, has shown efficacy in a few cases of BP [70,71]. Noteworthy, BP development has paradoxically been reported during ustekinumab treatment [72,73]. It is unclear whether such effect may be a consequence of IL-12 or rather IL-23 downregulation. Thus, because of the recent development of specific IL23 inhibitors, such as guselkumab, risankizumab, mirikizumab, and tildrakizumab, further studies are warranted www.sciencedirect.com
to clarify whether IL-23 inhibitors could have such a place in BP management [74]. Like IL-17 and IL-23, the chemokine CXCL-10, which is also functionally related to IL-17-driven inflammation and could also promote MMP-9 secretion, was shown to correlate with BP relapse within the first year of treatment [75]. MMP-9 secretion is in turn dependent on the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen associated protein kinase (MAPK) and phosphoinositide-3 kinase [75]. In a study by Hellberg et al. inhibitors of p38-MAPK or ERK1/2 phosphorylation blocked autoantibody- or irritant-induced neutrophil-dependent inflammation in mice in a similar manner as methylprednisolone [76]. All these findings provide support for an intriguing therapeutic scenario of targeting these intracellular pathways in BP. Finally, targeting complement activation might be also an effective strategy. It is well known that C3 deposits along the BMZ lead to formation of the complement fraction C3a and C5a, which act as potent chemoattractants for neutrophils. Specifically, C5a interaction with C5a receptor 1 (C5aR1) promotes the arrest of neutrophils on the endothelium and release of leukotriene B4 (LTB4), which induce migration of neutrophils to the interstitial space through an autocrine/paracrine circuit [77,78]. In a study published by Kasprick et al. TNT003, a mouse monoclonal antibody directed against the complement fraction C1s, inhibited IgG induced complement activation, including C3 deposition and C3a and C5a formation, in a human skin cryosection assay [79]. Sutimlimab, a humanized anti C1s monoclonal antibody, has proven to be safe and well tolerated in a phase I, first-in-human, double-blind, randomized, placebo-controlled trial, including 64 healthy volunteers (Table 2), and a therapeutic trial in BP may be expected to come in the next few months [80]. Finally targeting C5a and/or LTB4 may also hold promise in downregulating the immune pathogenesis of BP. Current Opinion in Pharmacology 2019, 46:34–43
40 Dermatology
Figure 2
SUTILMIMAB
IL-6
Eotaxin
Eosinophilic
IL-8
granulocyte BERTILIMUMAB
C3a
C5a
Neutrophilic granulocyte IL-17
IL-4
Eotaxin
IL-5
Mast cell
IL-4
OMALIZUMAB
DUPILUMAB
IL-5
Th17 IL-4 BP180 IgG anti-BP180
Th2
IXEKIZUMAB
MEPOLIZUMAB
Mast cell
granulocytes
C3 IgE anti BP180
Eosinophilic
B cells Current Opinion in Pharmacology
Representative figure showing how new targeted therapies interfere with key pathogenic events in pemphigoid. Skin blistering in pemphigoid occurs through complement-dependent and complement-independent mechanisms. IgG binding to BP180 leads to complement activation, C3 deposition and formation of C3a and C5a, which in turn induce mast cell degranulation and act also as potent chemotactic molecules stimulating inflammatory cells recruitment. IgE targeting BP180 is also present and can activate both mast cells and eosinophils through the FceR. Omalizumab, a human monoclonal anti IgE antibody prevents IgE binding to eosinophils and mast cells and consequently their activation. Sutimlimab is a monoclonal anti C1s antibody which blocks complement activation; TNT003, a mouse anti C1s monoclonal antibody demonstrated inhibition of IgG induced complement activation in a pre-clinical study on bullous pemphigoid skin cryosections. Activation of eosinophils and the T-helper 2-eosinophil cross-talk play a key role in sustaining autoantibody production by B-cells and driving tissue damage in pemphigoid. Bertilimumab is a monoclonal antibody targeting eotaxin, a leading cytokine involved in eosinophil recruitment and activation. Likewise targeting IL-5 and IL-4 may also be beneficial in pemphigoid; mepolizumab and dupilumab are monoclonal antibodies targeting IL-5 and IL-4 respectively; both cytokines are involved in eosinophil activation; IL-4 also stimulate B-cells to produce autoantibodies. Finally IL-17 may also play a role in pemphigoid, mostly by activating neutrophil granulocytes, thus accounting for a therapeutic application of IL-17 inhibitors (e.g. ixekizumab). Abbreviations in the figure: IL = interleukin; Th = T helper cell.
of special interest of outstanding interest
Figure 2 summarizes the mode of action of new monoclonal antibodies, which are currently tried in BP. 1.
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Conflict of interest statement Nothing declared.
Acknowledgements This review was in part supported by grants of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) He 1602/ 13-2 and FOR 2497 Pegasus (to MH).
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9.
Benzaquen M, Borradori L, Berbis P, Cazzaniga S, Valero R, Richard MA et al.: Dipeptidyl peptidase IV inhibitors, a risk factor for bullous pemphigoid: retrospective multicenter casecontrol study from France and Switzerland. J Am Acad Dermatol 2018, 78:1090-1096.
10. Bastuji-Garin S, Joly P, Lemordant P, Sparsa A, Bedane C, Delaporte E et al.: Risk factors for bullous pemphigoid in the elderly: a prospective case-control study. J Invest Dermatol 2011, 131:637-643. 11. Lloyd-Lavery A, Chi CC, Wojnarowska F, Taghipour K: The associations between bullous pemphigoid and drug use: a UK case-control study. JAMA Dermatol 2013, 149:58-62. 12. Kridin K, Bergman R: Association of Bullous Pemphigoid with Dipeptidyl-Peptidase 4 Inhibitors in Patients With Diabetes: Estimating the Risk of the New Agents and Characterizing bullous pemphigoid with dipeptidylpeptidase 4 inhibitors in patients with diabetes: estimating the risk of the new agents and characterizing the patients. JAMA Dermatol 2018, 154:1152-1158. This retrospective case-control study clearly demonstrates that the intake of vidagliptin and linagliptin are associated with an increased risk of bullous pemphigoid 13. Zhao CY, Hwang SJE, Consuegra G, Chou S, Fernandez-Penas P: Anti-programmed cell death-1 therapy-associated bullous disorders: a systematic review of the literature. Melanoma Res 2018, 28:491-501. 14. Lamberts A, Meijer JM, Jonkman MF: Nonbullous pemphigoid: a systematic review. J Am Acad Dermatol 2018, 78:989-995 e2. 15. Murrell DF, Daniel BS, Joly P, Borradori L, Amagai M, Hashimoto T et al.: Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts. J Am Acad Dermatol 2012, 66:479-485. 16. Feliciani C, Caldarola G, Kneisel A, Podstawa E, Pfutze M, Pfutzner W et al.: IgG autoantibody reactivity against bullous pemphigoid (BP) 180 and BP230 in elderly patients with pruritic dermatoses. Br J Dermatol 2009, 161:306-312.
23. Joly P, Roujeau JC, Benichou J, Picard C, Dreno B, Delaporte E et al.: A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002, 346:321-327. 24. Sticherling M, Franke A, Aberer E, Glaser R, Hertl M, Pfeiffer C et al.: An open, multicentre, randomized clinical study in patients with bullous pemphigoid comparing methylprednisolone and azathioprine with methylprednisolone and dapsone. Br J Dermatol 2017, 177:1299-1305. 25. Kridin K, Schwartz N, Cohen AD, Zelber-Sagi S: Mortality in bullous pemphigoid: a systematic review and meta-analysis of standardized mortality ratios. J Dermatol 2018, 45:1094-1100. 26. Henehan M, Montuno M, De Benedetto A: Doxycycline as an anti-inflammatory agent: updates in dermatology. J Eur Acad Dermatol Venereol 2017, 31:1800-1808. 27. Budni J, Garcez ML, de Medeiros J, Cassaro E, Bellettini-Santos T, Mina F et al.: The anti-inflammatory role of minocycline in Alzheimer’s disease. Curr Alzheimer Res 2016, 13:1319-1329. 28. Sanchez Miralles E, Nunez Cabezon M, Ledo Pozueta A: Treatment of generalized bullous pemphigoid with oral tetracycline. J Am Acad Dermatol 1994, 30:291. 29. Fivenson DP, Breneman DL, Rosen GB, Hersh CS, Cardone S, Mutasim D: Nicotinamide and tetracycline therapy of bullous pemphigoid. Arch Dermatol 1994, 130:753-758. 30. Williams HC, Wojnarowska F, Kirtschig G, Mason J, Godec TR, Schmidt E et al.: Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, noninferiority, randomised controlled trial. Lancet 2017, 389:1630-1638. This study illustrated, for the first time and in a large patients cohort, that doxycycline shows comparable efficacy but decreased incidence of adverse events compared to prednisolone for the initial therapeutic control of bullous pemphigoid 31. Mason JM, Chalmers JR, Godec T, Nunn AJ, Kirtschig G, Wojnarowska F et al.: Doxycycline compared with prednisolone therapy for patients with bullous pemphigoid: costeffectiveness analysis of the BLISTER trial. Br J Dermatol 2018, 178:415-423. The cost- effectiveness analysis of the BLISTER trial highlighted that prednisolone has to be preferred over doxycycline in patients with severe forms of bullous pemphigoid, due to higher efficacy and reduced costs 32. Sladden MJ, Hutchinson PE: The BLISTER study: possible overestimation of tetracycline efficacy. Lancet 2017, 390:735.
17. Fania L, Caldarola G, Muller R, Brandt O, Pellicano R, Feliciani C et al.: IgE recognition of bullous pemphigoid (BP)180 and BP230 in BP patients and elderly individuals with pruritic dermatoses. Clin Immunol 2012, 143:236-245.
33. Vakharia PP, Nardone B, Schlosser BJ, Lee D, Serrano L, West DP: Chronic exposure to tetracyclines and subsequent diagnosis for non-melanoma skin cancer in a large Midwestern U.S. patient population. J Eur Acad Dermatol Venereol 2017, 31: e534-e536.
18. Daneshpazhooh M, Ghiasi M, Lajevardi V, Nasiri N, Balighi K, Teimourpour A et al.: BPDAI and ABSIS correlate with serum anti-BP180 NC16A IgG but not with anti-BP230 IgG in patients with bullous pemphigoid. Arch Dermatol Res 2018, 310:255-259.
34. Amber KT, Maglie R, Solimani F, Eming R, Hertl M: Targeted therapies for autoimmune bullous diseases: current status. Drugs 2018, 78:1527-1548 http://dx.doi.org/10.1007/s40265-0180976-5.
19. Levy-Sitbon C, Barbe C, Plee J, Goeldel AL, Antonicelli F, Reguiai Z et al.: Assessment of bullous pemphigoid disease area index during treatment: a prospective study of 30 patients. Dermatology 2014, 229:116-122.
35. Li N, Culton D, Diaz LA, Liu Z: Modes of action of intravenous immunoglobulin in bullous pemphigoid. J Invest Dermatol 2018, 138:1249-1251.
20. Zheng M, Ujiie H, Muramatsu K, Sato-Matsumura KC, Maeda T, Ujiie I et al.: A possible association between BP230-type www.sciencedirect.com
36. Kamaguchi M, Iwata H, Mori Y, Toyonaga E, Ujiie H, Kitagawa Y et al.: Anti-idiotypic antibodies against BP-IgG prevent type XVII collagen depletion. Front Immunol 2017, 8:1669. Current Opinion in Pharmacology 2019, 46:34–43
42 Dermatology
37. Sasaoka T, Ujiie H, Nishie W, Iwata H, Ishikawa M, Higashino H et al.: Intravenous IgG reduces pathogenic autoantibodies, serum IL-6 levels, and disease severity in experimental bullous pemphigoid models. J Invest Dermatol 2018, 138:1260-1267. 38. Gaitanis G, Alexis I, Pelidou SH, Gazi IF, Kyritsis AP, Elisaf MS et al.: High-dose intravenous immunoglobulin in the treatment of adult patients with bullous pemphigoid. Eur J Dermatol 2012, 22:363-369. 39. Ahmed AR: Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 2001, 45:825-835. 40. Amagai M, Ikeda S, Hashimoto T, Mizuashi M, Fujisawa A, Ihn H et al.: A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid. J Dermatol Sci 2017, 85:77-84. This is the first multicenter, randomized, placebo-controlled, double-blind trial confirming that intravenous immunoglobulins are a highly effective therapy for difficult-to-treat bullous pemphigoid 41. Hall RP 3rd, Streilein RD, Hannah DL, McNair PD, Fairley JA, Ronaghy A et al.: Association of serum B-cell activating factor level and proportion of memory and transitional B cells with clinical response after rituximab treatment of bullous pemphigoid patients. J Invest Dermatol 2013, 133:2786-2788. 42. Lourari S, Herve C, Doffoel-Hantz V, Meyer N, Bulai-Livideanu C, Viraben R et al.: Bullous and mucous membrane pemphigoid show a mixed response to rituximab: experience in seven patients. J Eur Acad Dermatol Venereol 2011, 25:1238-1240. 43. Shetty S, Ahmed AR: Treatment of bullous pemphigoid with rituximab: critical analysis of the current literature. J Drugs Dermatol 2013, 12:672-677. 44. Lamberts A, Euverman HI, Terra JB, Jonkman MF, Horvath B: Effectiveness and safety of rituximab in recalcitrant pemphigoid diseases. Front Immunol 2018, 9:248. 45. Cho YT, Chu CY, Wang LF: First-line combination therapy with rituximab and corticosteroids provides a high complete remission rate in moderate-to-severe bullous pemphigoid. Br J Dermatol 2015, 173:302-304. 46. Ahmed AR, Shetty S, Kaveri S, Spigelman ZS: Treatment of recalcitrant bullous pemphigoid (BP) with a novel protocol: Aa retrospective study with a 6-year follow-up. J Am Acad Dermatol 2016, 74:700-708 e3. Although this is a retrospective study on few patients, it clearly supports the efficacy of a combination therapy with intravenous immunoglobulin and rituximab for patients with recalcitrant bullous pemphigoid 47. Kolesnik M, Becker E, Reinhold D, Ambach A, Heim MU, Gollnick H et al.: Treatment of severe autoimmune blistering skin diseases with combination of protein A immunoadsorption and rituximab: a protocol without initial high dose or pulse steroid medication. J Eur Acad Dermatol Venereol 2014, 28:771-780. 48. Kasperkiewicz M, Schulze F, Meier M, van Beek N, Nitschke M, Zillikens D et al.: Treatment of bullous pemphigoid with adjuvant immunoadsorption: a case series. J Am Acad Dermatol 2014, 71:1018-1020. 49. Hubner F, Kasperkiewicz M, Knuth-Rehr D, Shimanovich I, Hubner J, Sufke S et al.: Adjuvant treatment of severe/ refractory bullous pemphigoid with protein A immunoadsorption. J Dtsch Dermatol Ges 2018, 16:1109-1118. 50. Freire PC, Munoz CH, Stingl G: IgE autoreactivity in bullous pemphigoid: eosinophils and mast cells as major targets of pathogenic immune reactants. Br J Dermatol 2017, 177:1644-1653. This study demonstrates that IgE targeting BP180 directly activate eosinophils and mast cells, in bullous pemphigoid 51. London VA, Kim GH, Fairley JA, Woodley DT: Successful treatment of bullous pemphigoid with omalizumab. Arch Dermatol 2012, 148:1241-1243. 52. Yalcin AD, Genc GE, Celik B, Gumuslu S: Anti-IgE monoclonal antibody (omalizumab) is effective in treating bullous Current Opinion in Pharmacology 2019, 46:34–43
pemphigoid and its effects on soluble CD200. Clin Lab 2014, 60:523-524. 53. Menzinger S, Kaya G, Schmidt E, Fontao L, Laffitte E: Biological and clinical response to omalizumab in a patient with bullous pemphigoid. Acta Derm Venereol 2018, 98:284-286. 54. Balakirski G, Alkhateeb A, Merk HF, Leverkus M, Megahed M: Successful treatment of bullous pemphigoid with omalizumab as corticosteroid-sparing agent: report of two cases and review of literature. J Eur Acad Dermatol Venereol 2016, 30:1778-1782. This work summarizes the evidence supporting omalizumab use in patients with bullous pemphigoid who failed conventional immunosuppressive therapy 55. Yu KK, Crew AB, Messingham KA, Fairley JA, Woodley DT: Omalizumab therapy for bullous pemphigoid. J Am Acad Dermatol 2014, 71:468-474. 56. Kremer N, Snast I, Cohen ES, Hodak E, Mimouni D, Lapidoth M et al.: Rituximab and omalizumab for the treatment of bullous pemphigoid: a systematic review. Am J Clin Dermatol 2018 http://dx.doi.org/10.1007/s40257-018-0401-6. Systematic review analyzing the still-limited data on the use of two monoclonal antibodies, rituximab and omalizumab, in patients with recalcitrant bullous pemphigoid 57. Saniklidou AH, Tighe PJ, Fairclough LC, Todd I: IgE autoantibodies and their association with the disease activity and phenotype in bullous pemphigoid: a systematic review. Arch Dermatol Res 2018, 310:11-28. 58. Amber KT, Zikry J, Hertl M: A multi-hit hypothesis of bullous pemphigoid and associated neurological disease: is HLADQB103:01, a potential link between immune privileged antigen exposure and epitope spreading? HLA 2017, 89:127-134. 59. Thoma-Uszynski S, Uter W, Schwietzke S, Schuler G, Borradori L, Hertl M: Autoreactive T and B cells from bullous pemphigoid (BP) patients recognize epitopes clustered in distinct regions of BP180 and BP230. J Immunol 2006, 176:2015-2023. 60. Budinger L, Borradori L, Yee C, Eming R, Ferencik S, GrosseWilde H et al.: Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls. J Clin Invest 1998, 102:2082-2089. 61. Hofmann S, Thoma-Uszynski S, Hunziker T, Bernard P, Koebnick C, Stauber A et al.: Severity and phenotype of bullous pemphigoid relate to autoantibody profile against the NH2and COOH-terminal regions of the BP180 ectodomain. J Invest Dermatol 2002, 119:1065-1073. 62. Giomi B, Caproni M, Calzolari A, Bianchi B, Fabbri P: Th1, Th2 and Th3 cytokines in the pathogenesis of bullous pemphigoid. J Dermatol Sci 2002, 30:116-128. 63. Gounni Abdelilah S, Wellemans V, Agouli M, Guenounou M, Hamid Q, Beck LA et al.: Increased expression of Th2associated chemokines in bullous pemphigoid disease. Role of eosinophils in the production and release of these chemokines. Clin Immunol 2006, 120:220-231. 64. Amber KT, Valdebran M, Kridin K, Grando SA: The role of eosinophils in bullous pemphigoid: a developing model of eosinophil pathogenicity in mucocutaneous disease. Front Med (Lausanne) 2018, 5:201. This review article summarizes in a clear manner the different inflammatory pathways centred on the activation of eosinophils in bullous pemphigoid, which may represents suitable therapeutic targets in the future 65. Lee J, Werth VP, Hall RP 3rd, Eming R, Fairley JA, Fajgenbaum DC et al.: Perspective from the 5th international pemphigus and pemphigoid foundation scientific conference. Front Med (Lausanne) 2018, 5:306. 66. Kaye A, Gordon SC, Deverapalli SC, Her MJ, Rosmarin D: Dupilumab for the treatment of recalcitrant bullous pemphigoid. JAMA Dermatol 2018, 154(10):1225-1226 http://dx. doi.org/10.1001/jamadermatol.2018.2526. This is the first published work addressing the efficacy of dupilumab, an anti-IL4 monoclonal antibody, in a patient with recalcitrant bullous pemphigoid www.sciencedirect.com
Emerging therapies in pemphigoid Maglie and Hertl 43
67. Le Jan S, Plee J, Vallerand D, Dupont A, Delanez E, Durlach A et al.: Innate immune cell-produced IL-17 sustains inflammation in bullous pemphigoid. J Invest Dermatol 2014, 134:2908-2917. This elegant study demonstrates that IL-17 may be directly implicated in the blister formation process in BP by increasing the release of proteases originated from activated neutrophils 68. Chakievska L, Holtsche MM, Kunstner A, Goletz S, Petersen BS, Thaci D et al.: IL -17A is functionally relevant and a potential therapeutic target in bullous pemphigoid. J Autoimmun 2019, 96:104-112 http://dx.doi.org/10.1016/j.jaut.2018.09.003. This study shows that inhibition of IL-17 in a mouse model of bullous pemphigoid reduced the formation of blisters, providing the rationale for investigating the usefulness of such a therapeutic approach in humans 69. Plee J, Le Jan S, Giustiniani J, Barbe C, Joly P, Bedane C et al.: Integrating longitudinal serum IL-17 and IL-23 follow-up, along with autoantibodies variation, contributes to predict bullous pemphigoid outcome. Sci Rep 2015, 5:18001. This study identifies baseline serum levels of IL-17 and IL-23 as predictors of bullous pemphigoid severity during the disease course 70. Loget J, Plee J, Antonicelli F, Bernard P: A successful treatment with ustekinumab in a case of relapsing bullous pemphigoid associated with psoriasis. J Eur Acad Dermatol Venereol 2017, 31:e228-e230. 71. Majima Y, Yagi H, Tateishi C, Groth S, Schmidt E, Zillikens D et al.: A successful treatment with ustekinumab in a case of antilaminin-gamma1 pemphigoid associated with psoriasis. Br J Dermatol 2013, 168:1367-1369. 72. Onsun N, Sallahoglu K, Dizman D, Su O, Tosuner Z: Bullous pemphigoid during ustekinumab therapy in a psoriatic patient. Eur J Dermatol 2017, 27:81-82. 73. Le Guern A, Alkeraye S, Vermersch-Langlin A, Coupe P, Vonarx M: Bullous pemphigoid during ustekinumab therapy. JAAD Case Rep 2015, 1:359-360. 74. Ibler E, Gordon KB: IL-23 inhibitors for moderate-to-severe psoriasis. Semin Cutan Med Surg 2018, 37:158-162. 75. Riani M, Le Jan S, Plee J, Durlach A, Le Naour R, Haegeman G et al.: Bullous pemphigoid outcome is associated with CXCL10-induced matrix metalloproteinase 9 secretion from
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monocytes and neutrophils but not lymphocytes. J Allergy Clin Immunol 2017, 139:863-872 e3. 76. Hellberg L, Samavedam U, Holdorf K, Hansel M, Recke A, Beckmann T et al.: Methylprednisolone blocks autoantibodyinduced tissue damage in experimental models of bullous pemphigoid and epidermolysis bullosa acquisita through inhibition of neutrophil activation. J Invest Dermatol 2013, 133:2390-2399. This study shows that intracellular molecules including Akt, ERK1/2, and p38 MAPK are potential therapeutic targets in bullous pemphigoid 77. Sezin T, Krajewski M, Wutkowski A, Mousavi S, Chakievska L, Bieber K et al.: The leukotriene B4 and its receptor BLT1 act as critical drivers of neutrophil recruitment in murine bullous pemphigoid-like epidermolysis bullosa acquisita. J Invest Dermatol 2017, 137:1104-1113. This study provides rationale for targeting LTB4 to impair neutrophils recruitment in sub-epidermal blistering dermatosis 78. Sadik CD, Miyabe Y, Sezin T, Luster AD: The critical role of C5a as an initiator of neutrophil-mediated autoimmune inflammation of the joint and skin. Semin Immunol 2018, 37:21-29. This review article summarizes the mechanisms by which complement activation and C5a formation promotes neutrophils accumulation in pemphigoid diseases 79. Kasprick A, Holtsche MM, Rose EL, Hussain S, Schmidt E, Petersen F, Panicker S, Ludwig RJ: The Anti-C1s Antibody TNT003 Prevents Complement Activation in the Skin Induced by Bullous Pemphigoid Autoantibodies. J Invest Dermatol 2018, 138:458-461. Thisin vitro study shows that inhibition of C1s reduces complement activation in bullous pemphigoid 80. Bartko J, Schoergenhofer C, Schwameis M, Firbas C, Beliveau M, Chang C, Marier JF, Nix D, Gilbert JC, Panicker S, Jilma B: A Randomized, First-in-Human, Healthy Volunteer Trial of sutimlimab, a Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway. Clin Pharmacol Ther 2018, 104(4):655-663. This is the first study in humans showing that sutimlimab has a good safety profile and may be potentially useful for inhibition of the classical complement pathway, that play a major pathogenic role in several autoimmune diseases, including bullous pemphigoid
Current Opinion in Pharmacology 2019, 46:34–43
ScienceDirect Pharmacological advances in pemphigoid Roberto Maglie1,2 and Michael Hertl1 Pemphigoid is the most common autoimmune blistering disease. IgG and IgE autoantibodies against the hemidesmosomal antigens Bullous Pemphigoid (BP) 180 and BP230 are of pathogenic relevance, since autoantibody– antigen binding results in complement activation, immune cells infiltration, impaired hemidesmosomal function, and loss of dermal–epidermal adhesion. Systemic steroids and immunosuppressants are frontline therapies in pemphigoid, but result in substantial morbidity and increased mortality. A large randomized multicenter study highlighted doxycycline as a feasible alternative to systemic corticosteroids in patients not suitable for long-term steroid use. In recent years, new targeted therapies, including intravenous immunoglobulin (IvIg), rituximab, omalizumab, and immunoadsorption, have proven efficacy in the refractory setting, but, with the exception of IVIG, large randomized trial has not been performed yet. Basic research studies have now shed light on the pathogenic role of eosinophils and autoreactive T-helper 2 cells in pemphigoid, inducing tissue damage and sustaining autoantibody production by autoreactive B-cells, respectively. Indeed, eosinophils and Th2-related cytokines have become attractive therapeutic options. Moreover, Interleukin-17 related inflammatory pathways have been also shown to participate in the blistering process. This review discusses current evidence for the use of targeted therapies in pemphigoid as well as most relevant pharmacologic advances and new drugs currently under clinical investigation. Addresses 1 Department of Dermatology, Philipps University, Baldingerstr., Marburg, Germany 2 Department of Surgical and Translational Medicine, Section of Dermatology, University of Florence, Florence, Italy Corresponding authors: Maglie, Roberto ([email protected]), Hertl, Michael ([email protected])
Current Opinion in Pharmacology 2019, 46:34–43 This review comes from a themed issue on Dermatology Edited by Sonja Sta¨nder and Mette Deleuran
https://doi.org/10.1016/j.coph.2018.12.007 1471-4892/ã 2018 Elsevier Ltd. All rights reserved.
Introduction Pemphigoid, or bullous pemphigoid (BP) or cutaneous pemphigoid, represents the most common autoimmune Current Opinion in Pharmacology 2019, 46:34–43
blistering dermatoses. It is a B-cell driven disease: selfreactive B-cells produce autoantibodies, mainly of the IgG subclass, against BP180 and BP230, proteins responsible for the adhesion of basal keratinocytes to the basement membrane zone (BMZ). Binding of IgG autoantibodies to BP180, and specifically to the BP180-NC16A subdomain, activates distinct inflammatory pathways, that is, complement activation, mast cell degranulation, release of pro-inflammatory cytokines and chemokines and recruitment of neutrophil and eosinophil granulocytes, and promotes the internalization and degradation of BP180 [1,2]. This leads to dermal–epidermal separation, which clinically corresponds to the appearance of skin blisters. In addition to BP180 NC16A IgG antibodies, BP patients may subsequently develop autoantibodies against other epitopes of both BP180 and BP230, a phenomenon referred to as epitope spreading, which has been demonstrated to correlate with the severity of BP in disease course [3–5]. Recently, specific IgE targeting the NC16A domain of BP180 has been identified and has been shown to play a supportive role in the pathogenesis of BP, mainly by triggering mast cell and eosinophil degranulation [5]. Specific serum IgE concentrations parallel disease activity, making them an attractive therapeutic target [6]. BP predominately affects the elderly (peak at 60– 80 years). Its annual incidence varies from 2.4 to 21.7 new cases per million population worldwide [7,8]. Noteworthy, the incidence of BP is increasing, possibly due to the association of BP with certain internal diseases, including neurologic disorders, diabetes mellitus, and malignancies [7,9]. Drugs are also a known trigger of BP. Two large case–control studies reported a statistically significant association of BP and chronic use of several drugs, with special regard to diuretics, including spironolactone and loop diuretics [10,11]. Other studies have recently confirmed the increased risk of developing BP among diabetic patients using dipeptidyl peptidase IV inhibitors, mostly vildagliptin and linagliptin [12]. Of note is also the increasing number of reports addressing BP as an emerging side effect of anticancer therapies including immune checkpoint inhibitors targeting programmed cell death (PD) 1 and PD ligand-1 [13]. Typically, BP manifests with tense blisters, arising from erythematous-urticarial plaques or non-inflamed skin (Figure 1). Atypical presentations, referred to as ‘nonbullous pemphigoid’, include erythematous patches, urticarial plaques, papules, nodules, excoriations, eczema, and erythroderma (Figure 1). Pruritus is always present and may occur as a prodromal symptom [1,14], thus www.sciencedirect.com
Emerging therapies in pemphigoid Maglie and Hertl 35
Figure 1
(c)
(a)
(b)
(d) Current Opinion in Pharmacology
(a) and (b): Different clinical manifestations of pemphigoid: (a) tense blisters arising on erythematous inflamed skin; (b) papules with crusts and excoriations due to intense itching; (c), (d) immunopathologic findings of pemphigoid: (c) direct immunofluorescence of perilesional skin reveals linear deposition of IgG and C3 at the basement membrane zone (BMZ); rarely linear IgE deposition could be also detected; (d) indirect immunofluorescence detects circulating anti BMZ IgG antibodies; on salt split skin, IgG antibodies are detected on the epidermal side of the BMZ.
highlighting the concept that BP should be suspected in patients, especially elderly, complaining of pruritus with normal appearing skin. As per expert consensus recommendation, the presence of pruritus is sufficient for establishing the diagnosis of BP, if specific immunopathologic criteria are fulfilled [15]. It is, however, remarkable that IgG reactivity against BP180 and BP230 as well as IgE reactivity against BP180 may be found in a small percentage of elderly patients with non BP pruritic dermatosis, thereby raising speculation on the existence of a pre-clinical disease stage [16,17]. Making the diagnosis of BP relies on the combination of clinical, histopathological, and immunopathological findings. Direct immunofluorescence (DIF) is the most sensitive and specific diagnostic tool, showing linear deposits of IgG and the C3 complement fraction along the BMZ (Figure 1). Assessing serum concentrations of circulating autoantibodies by means of Enzyme Linked Immunosorbent Assay (ELISA) not only is of diagnostic significance, but also serves as a tool for monitoring the disease status and response to treatment, since circulating IgG autoantibodies, and particularly anti-BP180 IgG, parallel both disease activity and severity, and correlate with the risk of mortality [1,4]. The pathogenic meaning of anti-BP230 autoantibodies is, however, controversial. Studies have shown the lack of correlation between such autoantibodies and clinical scores including the Bullous Pemphigoid Disease Area and Activity Index (BPDAI) and Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) [18,19]. In contrast, a minority of BP patients only present with antiBP230 serum IgG. In these patients, there is a weaker www.sciencedirect.com
deposition of IgG1, IgG3, and complement in the skin, whereas circulating autoantibodies are mainly of the IgG4 subclasses, explaining the milder clinical course compared to anti-BP180 IgG or anti-BP180/BP230 IgG type BP [20]. On the contrary, p-200 pemphigoid is a rare variant of the pemphigoids, where laminin-g-1 functions as the main antigenic target. These cases feature overlapping clinical and immunopathologic characteristics of BP and epidermolysis bullosa acquisita but show a more favorable clinical course like in classic BP [21]. Treating BP is largely based on immunosuppressants. Still, systemic glucocorticoids represent the mainstay of therapy [22]. In 2002, a randomized trial by Joly et al. demonstrated that applying superpotent topical steroids was as effective and safe as oral prednisone in patients with moderate BP and even superior and safer in patients with severe disease [23]. However, adherence to treatment can be quite challenging. Immunosuppressants (i.e. azathioprine, methotrexate, ciclosporin, mycophenolate mofetil) or immunomodulators (i.e. dapsone) are usually given in addition to oral glucocorticoids due to their steroid-sparing effect [22]. In light of a lack of large randomized trials, there is no clear-cut evidence to prefer one of these agents instead of another. A recent German multicenter prospective randomized trial compared the steroid-sparing effects of azathioprine and dapsone: both drugs were associated with a reduced one-year mortality and showed no differences in terms of safety; however, dapsone demonstrated a greater steroid sparing effect [24]. Current Opinion in Pharmacology 2019, 46:34–43
36 Dermatology
Long-term immunosuppression leads to major side effects, mostly infections, which partly account for the higher mortality seen in BP patients compared to the general population [25]. Indeed, there is an urgent need for developing new treatment strategies aimed at targeting-specific pathogenic disease pathways and, at the same time, with a more favorable safety profile in this high-risk patient population. This review indeed focuses on the main pharmacologic advances, from the use of tetracyclines as a first line treatment to newly developed targeted therapies, which are gaining major clinical application in the management of BP.
Doxycycline as a first line therapy in pemphigoid Doxycycline, a semisynthetic second generation tetracycline, is a bacteriostatic agent that inhibits bacterial protein synthesis by targeting the 30S subunit of bacterial ribosomes, and is active against a broad spectrum of grampositive and gram-negative bacteria. In addition, doxycycline, as well as other tetracyclines, exerts a plethora of anti-inflammatory effects, explaining its efficacy in inflammatory diseases of the skin, such as acne vulgaris [26]. Doxycycline has been shown to inhibit the activation of metalloproteinases, decrease leukocytes chemotaxis and down regulate many pro-inflammatory cytokines, including TNF-alfa, IL-6 and IL-8, which are all involved in blister formation in BP [26]. Because of its anti-microbial, anti-inflammatory and possibly neuroprotective properties [27], doxycycline has been considered as an attractive therapeutic strategy in BP. Several studies indicated rapid clearing of skin blisters along with a generally good safety profile using doxycyclines, or other tetracyclines, either alone or in combination with nicotinamide [28,29,30]. Most of them, however, lacked a randomized design and were limited by the small number of enrolled patients. In 2017, Williams et al. published the results of a large, multicenter, parallelgroup randomized, non-inferiority trial (the BLISTER study) comparing doxycycline 200 mg/day and oral prednisolone 0.5 mg/kg/day in patients with newly diagnosed BP. The study indicated that doxycycline was not inferior (assuming a predefined non-inferiority margin of 37%) to prednisolone in achieving disease control at 6 weeks, but safer in terms of rate of serious adverse events and treatment-related death over a 56-week period [30]. One year later, the same authors published the costeffectiveness analysis of the trial, showing that doxycycline had comparable costs and quality of life improvement as prednisolone in patients with low-to-moderate BP, whereas prednisolone resulted in a higher quality of life improvement and reduced costs in patients with severe BP [31]. The results of the BLISTER study have been a matter of major controversies. Some authors noted that the statistical design might have biased the results in favor of doxycycline. Controversial issues include: i) the generous predefined non-inferiority Current Opinion in Pharmacology 2019, 46:34–43
margin, ii) the fact that patients were allowed to use topical steroids, iii) the end-point for effectiveness assumed as three blisters or fewer instead of skin lesions clearance, and iv) the initial fixed 0.5 mg/kg/day prednisolone dose regardless of disease severity for patients randomized into the prednisolone group [32]. Although the data are still not convincing to prefer doxycycline over glucocorticoids as a first line therapy in BP, the BLISTER study has strengthened the potential usefulness of doxycycline, maybe combined with high potency topical steroids, in naı¨ve patients with low disease activity or with comorbidities limiting the use of systemic glucocorticoids. Moreover, doxycycline has emerged as a conceivable maintenance following an initial steroid tapering course, as a tool to reduce the cumulative steroid dose and the use of adjuvant immunosuppressants. However unmet concerns about long-term doxycycline use include the emergence of bacterial resistance as well as a possible enhanced risk of non-melanoma skin cancer (NMSC), conceivably related to the drug-induced phototoxycity [26,33].
Targeted therapies in pemphigoid Currently available targeted therapies are indicated as a therapeutic option for BP patients resistant to oral glucocorticoids and immunosuppressants. They include: intravenous immunoglobulins (IvIg), the anti CD20 monoclonal antibody, rituximab, immunoadsorption (IA) and the anti-IgE monoclonal antibody, omalizumab [22,34]. IvIg are a highly effective therapy in BP. IvIg have pleiotropic anti-inflammatory effects [34], yet their mode of action in BP remains only partly understood. IvIg may induce saturation of the FcRn receptor, thereby reducing pathogenic serum autoantibodies [35]. In cultured keratinocytes, IvIg were shown to prevent BP180 depletion induced by pathogenic antibodies through anti-idiotypic antibodies that inhibit autoantibody binding to BP180 [36]. Sasaoka et al. recently showed that IvIg induce reduction of circulating pathogenic antibodies, amelioration of skin fragility and disease severity in a dose-dependent manner both in the passive-transfer and active mouse BP model [37]. They also showed that IvIg downregulated the serum level of inflammatory cytokines and chemokines and reduced keratinocyte secretion of IL-6 both in vitro and in vivo [37]. Indeed several case reports and studies reported meaningful clinical response of severe/refractory BP following IvIg treatment [34,38,39]. Further, their clinical efficacy has been recently demonstrated in a randomized, placebo-controlled, double blind trial. Remarkably, no significant reduction of anti BP180 antibodies was observed between the IvIg group compared to placebo [40]. Rituximab, an anti CD20 chimeric IgG1 monoclonal antibody, has been also successfully tried in patients with www.sciencedirect.com
Emerging therapies in pemphigoid Maglie and Hertl 37
recalcitrant BP [41–43]. Although no randomized placebo controlled studies have been yet conducted in BP, rituximab seems to be less effective in BP compared to pemphigus [44]. Response to treatment is also delayed (about four months, compared to two months for pemphigus) [44], thus suggesting that depletion of self-reactive B-cells and decrease of circulating anti-BP180 antibodies may not impair other critical pathogenic pathways of the disease. Nevertheless, first line rituximab treatment resulted in reduced one-year mortality compared with standard glucocorticoid therapy alone in one retrospective study [45], providing support for a more beneficial application of rituximab in the untreated disease than in the recalcitrant one. Further, combining rituximab with IvIg or immunoadsorption (IA) also demonstrated efficacy [46,47,48]. IA treatment relies on the selective removal of IgG antibodies from the plasma. Besides lowering serum concentrations of pathogenic IgG autoantibodies, IA likely causes their redistribution from the skin to the systemic circulation, preventing IgG binding to the cognate skin antigen. IA is an expensive treatment; side effects, including bacterial sepsis secondary to catheter infections, are also relevant [34]. However, IA has been shown to be of clinical benefit in patients with high disease activity and elevated serum autoantibodies levels. Two studies reported sustained remission using IA in combination with oral and topical glucocorticoids and dapsone in patients with untreated or recalcitrant BP. The reportedly prolonged decrease of anti BP180 autoantibodies following IA suggests that passive removal of circulating autoantibodies may downregulate their production through a yet unexplained mechanism. [48,49]. Several experimental studies support targeting IgE in BP. IgE binding to BP180 NC16A was shown to reduce the formation of hemidesmosomes via keratinocyte production of IL-6 and IL-8 [34]. Both mast cells and eosinophils express the high affinity IgE receptor, FceRI, and are activated by anti BP180 IgE/FceRI binding [50]. In a study by Lin et al. injection of anti BP180 NC16A IgE into mice expressing both human NC16A and FceRI resulted in skin eosinophil infiltration and blistering, whereas injection into NC16A/FceRI knockout mice did not [5]. However, despite positive clinical outcome reported in some case reports and series [6,34,51–53,54,55], the long-term efficacy of omalizumab in BP remains far less clear, since disease relapse seems to occur shortly following drug discontinuation [56]. Furthermore, identifying the ideal candidate for anti IgE directed therapy might be challenging. Accordingly, assessing serum titer of anti BP180 IgE by ELISA is not routinely available. Conversely studies aimed at correlating anti BP180 IgE with specific clinical phenotypes, that is presence of urticarial plaques, have yielded contrasting results [57]. www.sciencedirect.com
Although omalizumab may be considered as an option for patients with refractory disease, it is advisable to inform patients about its off-label use and the lack of evidence clearly supporting its efficacy and safety in BP. As a result, it may be considered after failure or in presence of contraindications to other third line therapies such as IvIg or rituximab; dosing total and specific IgE serum concentration can be recommended before treatment, although a direct link with treatment success has yet to be proven. Summary of the main relevant studies concerning targeted therapies currently in use for refractory BP are listed in Table 1.
Future therapeutic perspectives The association of BP with certain human leukocyte antigen (HLA) alleles, such as DQB1*03:01, which correspond to MHC-class II molecules, points to the involvement of autoreactive T helper cells in the pathogenesis of BP [58–60]. Accordingly, both IgG autoantibodies and Th cells from patients with BP were shown to recognize identical or similar epitopes of BP180 and even healthy individuals carrying BP predisposing alleles may show a peripheral T-cell response against BP180 [59–61]. However, in contrast to predisposed healthy individuals, BP patients show a predominant Th2-type response, suggesting that Th2 cells are primary involved in the loss of tolerance against BP180. Likewise, Th2-related cytokines, including IL-4 and IL-5, and chemokines, including eotaxin and monocyte chemoattractant protein 4 (MCP-4, also called CCL-13), are over represented in lesional BP skin, especially in the early phase of the disease [62,63]. Autoreactive Th2 cells are thought to exert a dual role in BP: they stimulate proliferation and autoantibody production by B-cells via CD40–CD40L interaction and contribute to eosinophil recruitment and activation. Eosinophil degranulation results in dermal– epidermal separation but also stimulates both Th cell polarization and Th2 cell recruitment via a paracrine feedback loop [63,64]. IL4, IL5, which are produced by Th2 cells and eosinophils, and eotaxin which is produced by both eosinophil and keratinocytes, are among the key regulators of the eosinophil-Th2 cell cross-talk in BP [64]; interestingly, a phase II study (NCT02226146) on the efficacy and safety of bertilimumab, a human monoclonal antibody targeting eotxain-1 has recently been completed. The results demonstrated an 81% reduction in disease severity, along with a significant steroid-sparing effect after only three bertilimumab infusions. The drug was well tolerated and no significant adverse event was reported [65]. Likewise, mepolizumab, an IL-5 inhibitor, is also under clinical evaluation in a phase II trial (NCT01705795). Conversely, Kaybe et al. have recently reported on the clinical efficacy of dupilumab, a monoclonal antibody Current Opinion in Pharmacology 2019, 46:34–43
38 Dermatology
Table 1 Summary of the main relevant studies, excluding case reports, on currently available targeted therapies indicated for the management of pemphigoid First author/year of publication
Study design
Number of Treatment schedule/dose patients
Intravenous immunoglobulin Ahmed, 2001 [39] Retrospective
15
Ahmed, 2016 [46]
12
Retrospective
Amagai, 2017 [40] Multicenter, randomized, placebo-controlled, double-blind Rituximab Lourari, 2011 [42]
56
IvIg 2 g/kg/cycle at 4-week intervals until clinical response and then at 6–8–10–12– 14–16 week intervals
Sustained clinical remission achieved in all cases, enabling successful steroid tapering. No significant adverse events were recorded. Clinical remission paralleled decreasing autoantibody concentrations. Phase 1: one IvIg cycle followed by Complete remission achieved in all patients. 8 weekly infusions of rituximab and then Relapse occurred in 2/10 patients. Re4 other rituximab infusions once a month; treatment with RTX led to complete remission phase 2: IvIg at monthly intervals; phase 3: in these patients. No serious adverse events IvIg at 6–8–10–12–14–16 week intervals recorded. 400 mg/kg/day for 5days (2 g/kg/cycle) Greater reduction of disease activity score at 15 days and through the observation period. Statistically significant reduction of DAS for severe cases (DAS 40). No serious adverse events recorded.
Retrospective (including patients with BP and MMP)
7
4 weekly i.v. infusions of 500 mg
Hall 3rd, 2013 [41]
Prospective
7
1000 mg i.v. at days 0 and 14
Cho, 2015 [45]
Retrospective (rituximab plus prednisone vs prednisone alone)
32
4 weekly infusions of 500 mg
28
500 mg or 1000 mg at days 0 and 14, followed by 500 mg at 6–12–18 months.
Immunoadsorption Kasperkiewiez, Open label pilot 2014 [48]
7
Protein A IA combined with oral prednisolone and dapsone
Hu¨bner, 2018 [49]
Case series
20
Protein A IA combined with oral prednisolone, dapsone and topical clobetasol
Omalizumab Yu, 2014 [55]
Open, non controlled 6
Lambert, 2018 [44] Retrospective (including patients with BP, MMP, EBA and DIGAL)
Balakirski, 2016 [54]
Case series
2
Synopsis
Among 4 patients with BP, two reported a complete response, one a partial response and one died 10 days following the first rituximab infusion. Clinical remission achieved in all cases enabling successful tapering of prednisone. Only 2 patients relapsed. Lower BAFF serum levels were associated with disease relapse. No serious adverse events recorded. Complete remission achieved in 90% of patients in the rituximab group. Patients in the rituximab group showed a slightly lower rate of infections and reduced 1-year mortality compared to the prednisone group. Rituximab at 1000 mg at days 0 and 14 was shown to be higher effective than at 500 mg. Among the BP included patients (n = 8), disease control was achieved in 83.3%, partial remission in 62.5%, and complete remission in 12.5%; 71.4% of patients relapsed. BP patients showed a poorer response (albeit not statistically significant) compared to MMP patients. One BP patient died due to bacterial sepsis. All patients achieved complete remission 1–3 months after IA; 6 of 7 patients showed longterm complete remission. 42% and 68% of patients were in complete remission at the 1-month and the last followup visit respectively; adverse events occurred in 65% of patients.
300 mg or 375 mg sc; dose intervals range: Significant improvement of disease activity, 2–8 weeks cessation of new blisters, amelioration of pruritus and decrease of immunosuppressants in 5 of 6 patients. No adverse events recorded 300 mg sc every 3 or 4 weeks Significant improvement of disease activity and cessation of pruritus was observed in both cases, enabling successful prednisone tapering. No adverse events recorded.
Abbreviations: IvIg, intravenous immunoglobulin; BP, bullous pemphigoid; BAFF, B-cell activating factor; MMP, mucous membrane pemphigoid; EBA, epidermolysis bullosa acquisita; LABD, linear IgA dermatosis; IA, immunoadsorption.
Current Opinion in Pharmacology 2019, 46:34–43
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Emerging therapies in pemphigoid Maglie and Hertl 39
Table 2 Summary of the main monoclonal antibodies, which represent future therapeutic perspective in pemphigoid Drug name
Class
Molecular target
Type of study/clinicaltrial.gov identifier
Bertilimumab
Human monoclonal antibody
Eotaxin-1
Mepolizumab
Human monoclonal antibody
IL-5
Dupilumab
Human monoclonal antibody
Ixekizumab
Human monoclonal antibody
IL-4 receptor subunit a IL17A
Sutilmimab
Human monoclonal antibody
C1s
Interventional, open label, phase 2; completed; NCT02226146. Results showed a 84% reduction of disease activity with a steroid sparing effect following 3 drug infusions. Interventional randomized, placebo-controlled, double-blind, phase 2; completed; NCT01705795 No clinical trials currently ongoing; efficacy reported in one case report [66]. Interventional, open-label, single-arm phase 2 study; recruiting; NCT03099538. No studies on BP currently ongoing; safety assessed in a phase I, first-in-human, double-blind, randomized, placebo-controlled study (NCT02502903).
Abbreviations: IL, Interleukin; C1s, C1s complement fraction.
against IL-4 and IL-13, in a case of refractory BP [66] (Table 2). Recent evidence also suggests the involvement of IL-17 in the pro-inflammatory amplication process in BP. IL-17 is elevated in the blister fluid and perilesional skin of BP patients and is produced by both lymphocytes and innate immune cells, including neutrophils and mast cells, under the influx of IL-6 and IL-23 [67,68]. IL-17 activates both human neutrophil elastase and MMP-9, which are crucial for the blister formation [67]. Accordingly, inhibition of IL-17A was shown to prevent dermal–epidermal splitting in cryosections of normal human skin incubated with anti-BP180 IgG and leukocytes. Serum IL-17A levels were also shown to correlate with disease severity in the passive transfer mouse model, suggesting that targeting IL-17 and its related pathways might be a therapeutic strategy in BP [68]. A clinical trial evaluating the efficacy of ixekizumab, a high-affinity fully human monoclonal antibody targeting IL17A, in patients with untreated and recalcitrant BP is currently ongoing (Table 2). IL-23 is the main molecule promoting over expression of IL-17. IL-23 was shown to be highly present in the blister fluid of BP patients [67]. A recent study by Ple´e et al. demonstrated that both IL-17 and IL-23 serum levels were elevated at the baseline in BP patients who experienced a relapse after initial disease control. Further, they postulated that IL-23 could also co-operate in BP pathogenesis independently from IL-17 and via induction of MMP-9 secretion by macrophages and dendritic cells [69]. Interestingly, ustekinumab, an inhibitor of IL-12 and IL-23, has shown efficacy in a few cases of BP [70,71]. Noteworthy, BP development has paradoxically been reported during ustekinumab treatment [72,73]. It is unclear whether such effect may be a consequence of IL-12 or rather IL-23 downregulation. Thus, because of the recent development of specific IL23 inhibitors, such as guselkumab, risankizumab, mirikizumab, and tildrakizumab, further studies are warranted www.sciencedirect.com
to clarify whether IL-23 inhibitors could have such a place in BP management [74]. Like IL-17 and IL-23, the chemokine CXCL-10, which is also functionally related to IL-17-driven inflammation and could also promote MMP-9 secretion, was shown to correlate with BP relapse within the first year of treatment [75]. MMP-9 secretion is in turn dependent on the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen associated protein kinase (MAPK) and phosphoinositide-3 kinase [75]. In a study by Hellberg et al. inhibitors of p38-MAPK or ERK1/2 phosphorylation blocked autoantibody- or irritant-induced neutrophil-dependent inflammation in mice in a similar manner as methylprednisolone [76]. All these findings provide support for an intriguing therapeutic scenario of targeting these intracellular pathways in BP. Finally, targeting complement activation might be also an effective strategy. It is well known that C3 deposits along the BMZ lead to formation of the complement fraction C3a and C5a, which act as potent chemoattractants for neutrophils. Specifically, C5a interaction with C5a receptor 1 (C5aR1) promotes the arrest of neutrophils on the endothelium and release of leukotriene B4 (LTB4), which induce migration of neutrophils to the interstitial space through an autocrine/paracrine circuit [77,78]. In a study published by Kasprick et al. TNT003, a mouse monoclonal antibody directed against the complement fraction C1s, inhibited IgG induced complement activation, including C3 deposition and C3a and C5a formation, in a human skin cryosection assay [79]. Sutimlimab, a humanized anti C1s monoclonal antibody, has proven to be safe and well tolerated in a phase I, first-in-human, double-blind, randomized, placebo-controlled trial, including 64 healthy volunteers (Table 2), and a therapeutic trial in BP may be expected to come in the next few months [80]. Finally targeting C5a and/or LTB4 may also hold promise in downregulating the immune pathogenesis of BP. Current Opinion in Pharmacology 2019, 46:34–43
40 Dermatology
Figure 2
SUTILMIMAB
IL-6
Eotaxin
Eosinophilic
IL-8
granulocyte BERTILIMUMAB
C3a
C5a
Neutrophilic granulocyte IL-17
IL-4
Eotaxin
IL-5
Mast cell
IL-4
OMALIZUMAB
DUPILUMAB
IL-5
Th17 IL-4 BP180 IgG anti-BP180
Th2
IXEKIZUMAB
MEPOLIZUMAB
Mast cell
granulocytes
C3 IgE anti BP180
Eosinophilic
B cells Current Opinion in Pharmacology
Representative figure showing how new targeted therapies interfere with key pathogenic events in pemphigoid. Skin blistering in pemphigoid occurs through complement-dependent and complement-independent mechanisms. IgG binding to BP180 leads to complement activation, C3 deposition and formation of C3a and C5a, which in turn induce mast cell degranulation and act also as potent chemotactic molecules stimulating inflammatory cells recruitment. IgE targeting BP180 is also present and can activate both mast cells and eosinophils through the FceR. Omalizumab, a human monoclonal anti IgE antibody prevents IgE binding to eosinophils and mast cells and consequently their activation. Sutimlimab is a monoclonal anti C1s antibody which blocks complement activation; TNT003, a mouse anti C1s monoclonal antibody demonstrated inhibition of IgG induced complement activation in a pre-clinical study on bullous pemphigoid skin cryosections. Activation of eosinophils and the T-helper 2-eosinophil cross-talk play a key role in sustaining autoantibody production by B-cells and driving tissue damage in pemphigoid. Bertilimumab is a monoclonal antibody targeting eotaxin, a leading cytokine involved in eosinophil recruitment and activation. Likewise targeting IL-5 and IL-4 may also be beneficial in pemphigoid; mepolizumab and dupilumab are monoclonal antibodies targeting IL-5 and IL-4 respectively; both cytokines are involved in eosinophil activation; IL-4 also stimulate B-cells to produce autoantibodies. Finally IL-17 may also play a role in pemphigoid, mostly by activating neutrophil granulocytes, thus accounting for a therapeutic application of IL-17 inhibitors (e.g. ixekizumab). Abbreviations in the figure: IL = interleukin; Th = T helper cell.
of special interest of outstanding interest
Figure 2 summarizes the mode of action of new monoclonal antibodies, which are currently tried in BP. 1.
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2.
Liu Y, Li L, Xia Y: BP180 is critical in the autoimmunity of bullous pemphigoid. Front Immunol 2017, 8:1752.
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4.
Di Zenzo G, Thoma-Uszynski S, Fontao L, Calabresi V, Hofmann SC, Hellmark T et al.: Multicenter prospective study of
Conflict of interest statement Nothing declared.
Acknowledgements This review was in part supported by grants of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) He 1602/ 13-2 and FOR 2497 Pegasus (to MH).
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37. Sasaoka T, Ujiie H, Nishie W, Iwata H, Ishikawa M, Higashino H et al.: Intravenous IgG reduces pathogenic autoantibodies, serum IL-6 levels, and disease severity in experimental bullous pemphigoid models. J Invest Dermatol 2018, 138:1260-1267. 38. Gaitanis G, Alexis I, Pelidou SH, Gazi IF, Kyritsis AP, Elisaf MS et al.: High-dose intravenous immunoglobulin in the treatment of adult patients with bullous pemphigoid. Eur J Dermatol 2012, 22:363-369. 39. Ahmed AR: Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 2001, 45:825-835. 40. Amagai M, Ikeda S, Hashimoto T, Mizuashi M, Fujisawa A, Ihn H et al.: A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid. J Dermatol Sci 2017, 85:77-84. This is the first multicenter, randomized, placebo-controlled, double-blind trial confirming that intravenous immunoglobulins are a highly effective therapy for difficult-to-treat bullous pemphigoid 41. Hall RP 3rd, Streilein RD, Hannah DL, McNair PD, Fairley JA, Ronaghy A et al.: Association of serum B-cell activating factor level and proportion of memory and transitional B cells with clinical response after rituximab treatment of bullous pemphigoid patients. J Invest Dermatol 2013, 133:2786-2788. 42. Lourari S, Herve C, Doffoel-Hantz V, Meyer N, Bulai-Livideanu C, Viraben R et al.: Bullous and mucous membrane pemphigoid show a mixed response to rituximab: experience in seven patients. J Eur Acad Dermatol Venereol 2011, 25:1238-1240. 43. Shetty S, Ahmed AR: Treatment of bullous pemphigoid with rituximab: critical analysis of the current literature. J Drugs Dermatol 2013, 12:672-677. 44. Lamberts A, Euverman HI, Terra JB, Jonkman MF, Horvath B: Effectiveness and safety of rituximab in recalcitrant pemphigoid diseases. Front Immunol 2018, 9:248. 45. Cho YT, Chu CY, Wang LF: First-line combination therapy with rituximab and corticosteroids provides a high complete remission rate in moderate-to-severe bullous pemphigoid. Br J Dermatol 2015, 173:302-304. 46. Ahmed AR, Shetty S, Kaveri S, Spigelman ZS: Treatment of recalcitrant bullous pemphigoid (BP) with a novel protocol: Aa retrospective study with a 6-year follow-up. J Am Acad Dermatol 2016, 74:700-708 e3. Although this is a retrospective study on few patients, it clearly supports the efficacy of a combination therapy with intravenous immunoglobulin and rituximab for patients with recalcitrant bullous pemphigoid 47. Kolesnik M, Becker E, Reinhold D, Ambach A, Heim MU, Gollnick H et al.: Treatment of severe autoimmune blistering skin diseases with combination of protein A immunoadsorption and rituximab: a protocol without initial high dose or pulse steroid medication. J Eur Acad Dermatol Venereol 2014, 28:771-780. 48. Kasperkiewicz M, Schulze F, Meier M, van Beek N, Nitschke M, Zillikens D et al.: Treatment of bullous pemphigoid with adjuvant immunoadsorption: a case series. J Am Acad Dermatol 2014, 71:1018-1020. 49. Hubner F, Kasperkiewicz M, Knuth-Rehr D, Shimanovich I, Hubner J, Sufke S et al.: Adjuvant treatment of severe/ refractory bullous pemphigoid with protein A immunoadsorption. J Dtsch Dermatol Ges 2018, 16:1109-1118. 50. Freire PC, Munoz CH, Stingl G: IgE autoreactivity in bullous pemphigoid: eosinophils and mast cells as major targets of pathogenic immune reactants. Br J Dermatol 2017, 177:1644-1653. This study demonstrates that IgE targeting BP180 directly activate eosinophils and mast cells, in bullous pemphigoid 51. London VA, Kim GH, Fairley JA, Woodley DT: Successful treatment of bullous pemphigoid with omalizumab. Arch Dermatol 2012, 148:1241-1243. 52. Yalcin AD, Genc GE, Celik B, Gumuslu S: Anti-IgE monoclonal antibody (omalizumab) is effective in treating bullous Current Opinion in Pharmacology 2019, 46:34–43
pemphigoid and its effects on soluble CD200. Clin Lab 2014, 60:523-524. 53. Menzinger S, Kaya G, Schmidt E, Fontao L, Laffitte E: Biological and clinical response to omalizumab in a patient with bullous pemphigoid. Acta Derm Venereol 2018, 98:284-286. 54. Balakirski G, Alkhateeb A, Merk HF, Leverkus M, Megahed M: Successful treatment of bullous pemphigoid with omalizumab as corticosteroid-sparing agent: report of two cases and review of literature. J Eur Acad Dermatol Venereol 2016, 30:1778-1782. This work summarizes the evidence supporting omalizumab use in patients with bullous pemphigoid who failed conventional immunosuppressive therapy 55. Yu KK, Crew AB, Messingham KA, Fairley JA, Woodley DT: Omalizumab therapy for bullous pemphigoid. J Am Acad Dermatol 2014, 71:468-474. 56. Kremer N, Snast I, Cohen ES, Hodak E, Mimouni D, Lapidoth M et al.: Rituximab and omalizumab for the treatment of bullous pemphigoid: a systematic review. Am J Clin Dermatol 2018 http://dx.doi.org/10.1007/s40257-018-0401-6. Systematic review analyzing the still-limited data on the use of two monoclonal antibodies, rituximab and omalizumab, in patients with recalcitrant bullous pemphigoid 57. Saniklidou AH, Tighe PJ, Fairclough LC, Todd I: IgE autoantibodies and their association with the disease activity and phenotype in bullous pemphigoid: a systematic review. Arch Dermatol Res 2018, 310:11-28. 58. Amber KT, Zikry J, Hertl M: A multi-hit hypothesis of bullous pemphigoid and associated neurological disease: is HLADQB103:01, a potential link between immune privileged antigen exposure and epitope spreading? HLA 2017, 89:127-134. 59. Thoma-Uszynski S, Uter W, Schwietzke S, Schuler G, Borradori L, Hertl M: Autoreactive T and B cells from bullous pemphigoid (BP) patients recognize epitopes clustered in distinct regions of BP180 and BP230. J Immunol 2006, 176:2015-2023. 60. Budinger L, Borradori L, Yee C, Eming R, Ferencik S, GrosseWilde H et al.: Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls. J Clin Invest 1998, 102:2082-2089. 61. Hofmann S, Thoma-Uszynski S, Hunziker T, Bernard P, Koebnick C, Stauber A et al.: Severity and phenotype of bullous pemphigoid relate to autoantibody profile against the NH2and COOH-terminal regions of the BP180 ectodomain. J Invest Dermatol 2002, 119:1065-1073. 62. Giomi B, Caproni M, Calzolari A, Bianchi B, Fabbri P: Th1, Th2 and Th3 cytokines in the pathogenesis of bullous pemphigoid. J Dermatol Sci 2002, 30:116-128. 63. Gounni Abdelilah S, Wellemans V, Agouli M, Guenounou M, Hamid Q, Beck LA et al.: Increased expression of Th2associated chemokines in bullous pemphigoid disease. Role of eosinophils in the production and release of these chemokines. Clin Immunol 2006, 120:220-231. 64. Amber KT, Valdebran M, Kridin K, Grando SA: The role of eosinophils in bullous pemphigoid: a developing model of eosinophil pathogenicity in mucocutaneous disease. Front Med (Lausanne) 2018, 5:201. This review article summarizes in a clear manner the different inflammatory pathways centred on the activation of eosinophils in bullous pemphigoid, which may represents suitable therapeutic targets in the future 65. Lee J, Werth VP, Hall RP 3rd, Eming R, Fairley JA, Fajgenbaum DC et al.: Perspective from the 5th international pemphigus and pemphigoid foundation scientific conference. Front Med (Lausanne) 2018, 5:306. 66. Kaye A, Gordon SC, Deverapalli SC, Her MJ, Rosmarin D: Dupilumab for the treatment of recalcitrant bullous pemphigoid. JAMA Dermatol 2018, 154(10):1225-1226 http://dx. doi.org/10.1001/jamadermatol.2018.2526. This is the first published work addressing the efficacy of dupilumab, an anti-IL4 monoclonal antibody, in a patient with recalcitrant bullous pemphigoid www.sciencedirect.com
Emerging therapies in pemphigoid Maglie and Hertl 43
67. Le Jan S, Plee J, Vallerand D, Dupont A, Delanez E, Durlach A et al.: Innate immune cell-produced IL-17 sustains inflammation in bullous pemphigoid. J Invest Dermatol 2014, 134:2908-2917. This elegant study demonstrates that IL-17 may be directly implicated in the blister formation process in BP by increasing the release of proteases originated from activated neutrophils 68. Chakievska L, Holtsche MM, Kunstner A, Goletz S, Petersen BS, Thaci D et al.: IL -17A is functionally relevant and a potential therapeutic target in bullous pemphigoid. J Autoimmun 2019, 96:104-112 http://dx.doi.org/10.1016/j.jaut.2018.09.003. This study shows that inhibition of IL-17 in a mouse model of bullous pemphigoid reduced the formation of blisters, providing the rationale for investigating the usefulness of such a therapeutic approach in humans 69. Plee J, Le Jan S, Giustiniani J, Barbe C, Joly P, Bedane C et al.: Integrating longitudinal serum IL-17 and IL-23 follow-up, along with autoantibodies variation, contributes to predict bullous pemphigoid outcome. Sci Rep 2015, 5:18001. This study identifies baseline serum levels of IL-17 and IL-23 as predictors of bullous pemphigoid severity during the disease course 70. Loget J, Plee J, Antonicelli F, Bernard P: A successful treatment with ustekinumab in a case of relapsing bullous pemphigoid associated with psoriasis. J Eur Acad Dermatol Venereol 2017, 31:e228-e230. 71. Majima Y, Yagi H, Tateishi C, Groth S, Schmidt E, Zillikens D et al.: A successful treatment with ustekinumab in a case of antilaminin-gamma1 pemphigoid associated with psoriasis. Br J Dermatol 2013, 168:1367-1369. 72. Onsun N, Sallahoglu K, Dizman D, Su O, Tosuner Z: Bullous pemphigoid during ustekinumab therapy in a psoriatic patient. Eur J Dermatol 2017, 27:81-82. 73. Le Guern A, Alkeraye S, Vermersch-Langlin A, Coupe P, Vonarx M: Bullous pemphigoid during ustekinumab therapy. JAAD Case Rep 2015, 1:359-360. 74. Ibler E, Gordon KB: IL-23 inhibitors for moderate-to-severe psoriasis. Semin Cutan Med Surg 2018, 37:158-162. 75. Riani M, Le Jan S, Plee J, Durlach A, Le Naour R, Haegeman G et al.: Bullous pemphigoid outcome is associated with CXCL10-induced matrix metalloproteinase 9 secretion from
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monocytes and neutrophils but not lymphocytes. J Allergy Clin Immunol 2017, 139:863-872 e3. 76. Hellberg L, Samavedam U, Holdorf K, Hansel M, Recke A, Beckmann T et al.: Methylprednisolone blocks autoantibodyinduced tissue damage in experimental models of bullous pemphigoid and epidermolysis bullosa acquisita through inhibition of neutrophil activation. J Invest Dermatol 2013, 133:2390-2399. This study shows that intracellular molecules including Akt, ERK1/2, and p38 MAPK are potential therapeutic targets in bullous pemphigoid 77. Sezin T, Krajewski M, Wutkowski A, Mousavi S, Chakievska L, Bieber K et al.: The leukotriene B4 and its receptor BLT1 act as critical drivers of neutrophil recruitment in murine bullous pemphigoid-like epidermolysis bullosa acquisita. J Invest Dermatol 2017, 137:1104-1113. This study provides rationale for targeting LTB4 to impair neutrophils recruitment in sub-epidermal blistering dermatosis 78. Sadik CD, Miyabe Y, Sezin T, Luster AD: The critical role of C5a as an initiator of neutrophil-mediated autoimmune inflammation of the joint and skin. Semin Immunol 2018, 37:21-29. This review article summarizes the mechanisms by which complement activation and C5a formation promotes neutrophils accumulation in pemphigoid diseases 79. Kasprick A, Holtsche MM, Rose EL, Hussain S, Schmidt E, Petersen F, Panicker S, Ludwig RJ: The Anti-C1s Antibody TNT003 Prevents Complement Activation in the Skin Induced by Bullous Pemphigoid Autoantibodies. J Invest Dermatol 2018, 138:458-461. Thisin vitro study shows that inhibition of C1s reduces complement activation in bullous pemphigoid 80. Bartko J, Schoergenhofer C, Schwameis M, Firbas C, Beliveau M, Chang C, Marier JF, Nix D, Gilbert JC, Panicker S, Jilma B: A Randomized, First-in-Human, Healthy Volunteer Trial of sutimlimab, a Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway. Clin Pharmacol Ther 2018, 104(4):655-663. This is the first study in humans showing that sutimlimab has a good safety profile and may be potentially useful for inhibition of the classical complement pathway, that play a major pathogenic role in several autoimmune diseases, including bullous pemphigoid
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