Dapsone Suppresses Disease in Preclinical Murine Models of Pemphigoid Diseases

Murthy, Sripriya; Schilf, Paul; Patzelt, Sabrina; Thieme, Markus; Becker, Mareike; Kröger, Lasse; Bremer, Tabea; Derenda-Hell, Aleksandra; Knebel, L.; Fagiani, Francesca; Ibrahim, Saleh M.; Schmidt, Enno; Zillikens, Detlef; Sadik, Christian D.

doi:10.1016/j.jid.2021.04.009

Cited by 20 publications

(11 citation statements)

References 34 publications

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“…In preclinical studies, investigators have highlighted the nonredundant roles of the anaphylatoxin C5a, an activation product of C5, and the eicosanoid leukotriene B 4 (LTB 4 ) in the development of inflammatory skin lesions in pemphigoid diseases . Both C5a and LTB 4 are also abundant in skin lesions of patients with bullous pemphigoid, suggesting that both may play a similar role in human disease.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Nomacopan for Treatment of Bullous Pemphigoid

et al. 2022

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IMPORTANCEBullous pemphigoid is a difficult-to-treat autoimmune blistering skin disease that predominantly affects older adults and is associated with an increased mortality rate.OBJECTIVE To examine the safety and therapeutic potential of nomacopan, an inhibitor of leukotriene B 4 and complement C5, in patients with bullous pemphigoid. DESIGN, SETTING, AND PARTICIPANTSThis multicenter, single-group, phase 2a nonrandomized controlled trial was conducted in the dermatology departments of universities in the Netherlands and Germany. Participants were enrolled between September 2018 and April 2020. Older adult patients (aged Ն55 years) with mild to moderate, new-onset or relapsing bullous pemphigoid were recruited into the study.INTERVENTIONS Patients received nomacopan, 90 mg, subcutaneously on day 1 and 30 mg subcutaneously daily until day 42. MAIN OUTCOMES AND MEASURESThe primary end point was the proportion of patients with grade 3 to 5 (severe) adverse events associated or possibly associated with nomacopan. Secondary end points included mean absolute and percentage changes in the Bullous Pemphigoid Disease Area Index (BPDAI) activity score, the BPDAI pruritus score, and the patient-reported outcome measures Dermatology Life Quality Index (DLQI) and Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL).RESULTS A total of 9 patients (median [range] age, 75 [55-85] years) with bullous pemphigoid were included in the trial, of whom 5 were women (55.6%). No serious adverse events associated with nomacopan were found. The mean (90% CI) BPDAI activity score decreased from 32.0 (8.7) points on day 1 to 19.6 (9.0) points on day 42. Seven of 9 patients (77.8%) responded to nomacopan with a reduction in the BPDAI activity score of at least 8 points between days 1 and 42; in 3 responders, the reduction was 80% or greater. On day 42, the mean (90% CI) BPDAI pruritus score had decreased by 6.8 (4.6) points from 17.6 (4.0) points on day 1. The mean (90% CI) DLQI score decreased from 11.3 (4.2) points at baseline to 6.4 (3.8) points by day 42, and the mean (90% CI) TABQOL score decreased from 14.6 (5.4) points at baseline to 10.3 (5.0) points on day 42. CONCLUSIONS AND RELEVANCEResults of this nonrandomized controlled trial suggest that nomacopan can be well tolerated in older patients with bullous pemphigoid and may have therapeutic benefits for suppressing acute flares of this disease. A larger, placebo-controlled randomized clinical trial is warranted to confirm this safety profile and to establish nomacopan as a new therapeutic option for bullous pemphigoid.

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Section: Introductionmentioning

confidence: 99%

Evaluation of Nomacopan for Treatment of Bullous Pemphigoid

et al. 2022

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“…The use of different mouse models for MMP could explain these discrepancies: the first study group induced MMP by passively transferring rabbit anti-laminin 332 IgG into neonatal mice, whereas the latter injected adult mice with rabbit anti-laminin 332 IgG against 2 immunodominant regions of laminin 332. Moreover, the latter mouse model was shown to fully replicate human disease, and dapsone, which is the first-choice in the therapeutic armamentarium of MMP, has proven effective in this passive MMP mouse model, thus further underlining its utility for the study of MMP ( 92 , 93 ). Nevertheless, more experimental studies are needed to clarify the impact of complement in the pathogenesis of MMP.…”

Section: Complement-dependent Pathogenic Pathways In Pdsmentioning

confidence: 99%

The relevance of complement in pemphigoid diseases: A critical appraisal

et al. 2022

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Pemphigoid diseases are autoimmune chronic inflammatory skin diseases, which are characterized by blistering of the skin and/or mucous membranes, and circulating and tissue-bound autoantibodies. The well-established pathomechanisms comprise autoantibodies targeting various structural proteins located at the dermal-epidermal junction, leading to complement factor binding and activation. Several effector cells are thus attracted and activated, which in turn inflict characteristic tissue damage and subepidermal blistering. Moreover, the detection of linear complement deposits in the skin is a diagnostic hallmark of all pemphigoid diseases. However, recent studies showed that blistering might also occur independently of complement. This review reassesses the importance of complement in pemphigoid diseases based on current research by contrasting and contextualizing data from in vitro, murine and human studies.

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“…Moreover, BP models induced by genetic deletion of BP180 pathogenic domains are characterized by spontaneous infiltration of granulocytes ( 94 ). Granulocytes induce blistering by different mechanisms such as the release of proteases, e.g., MMP-9, reactive oxygen species (ROS) and either neutrophil or eosinophil extracellular traps ( 51 , 92 , 95 – 97 ) ( Figure 1 ). In humans, neutrophils and eosinophils localize differently in BP skin, with the first predominating in the blister fluids and the second in the dermal skin ( 98 ).…”

Section: Cytokine Regulation Of Non T/b Immune Cells In Bullous Pemph...mentioning

confidence: 99%

The cytokine milieu of bullous pemphigoid: Current and novel therapeutic targets

et al. 2023

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Bullous pemphigoid (BP) is the most common autoimmune bullous disease, characterized by severe pruritus and skin blistering. The loss of tolerance against Collagen XVII, also referred to as BP180, is the main pathogenic event of BP, leading to production of IgG autoantibodies which mainly target the juxtamembranous extracellular non-collagenous 16th A (NC16A) domain of BP180. A complex inflammatory network is activated upon autoantibody binding to the basement membrane zone; this inflammatory loop involves the complement cascade and the release of several inflammatory cytokines, chemokines and proteases from keratinocytes, lymphocytes, mast cells and granulocytes. Collectively, these events disrupt the integrity of the dermal-epidermal junction, leading to subepidermal blistering. Recent advances have led to identify novel therapeutic targets for BP, whose management is mainly based on the long-term use of topical and systemic corticosteroids. As an example, targeting type-2 T-helper cell-associated cytokines, such as Interleukin-4 and interleukin-13 has shown meaningful clinical efficacy in case series and studies; targeting IL-17 and IL-23 has also been tried, owing to an important role of these cytokines in the chronic maintenance phase of BP. In this review article, we discuss the complex cytokine milieu that characterized BP inflammation, highlighting molecules, which are currently investigated as present and future therapeutic targets for this life-threatening disease.

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Dapsone Suppresses Disease in Preclinical Murine Models of Pemphigoid Diseases

Cited by 20 publications

References 34 publications

Evaluation of Nomacopan for Treatment of Bullous Pemphigoid

Evaluation of Nomacopan for Treatment of Bullous Pemphigoid

The relevance of complement in pemphigoid diseases: A critical appraisal

The cytokine milieu of bullous pemphigoid: Current and novel therapeutic targets

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