Pyoderma gangrenosum: proposed pathogenesis and current use of biologics with an emphasis on complement C5a inhibitor IFX-1

Lu, Justin D.; Milakovic, Milica; Ortega‐Loayza, Alex G.; Marzano, Angelo Valerio; Alavi, Afsáneh

doi:10.1080/13543784.2020.1819981

Cited by 21 publications

(26 citation statements)

References 32 publications

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“…Even if the secondary outcome results in favor of vilobelimab are preliminary, they still support a phase 3 trial where C5a inhibition is investigated, using 28‐day mortality as the primary endpoint [42]. The C5a antagonists vilobelimab and PMX‐53 thus constitute therapeutic prospects for ARDS in SARS CoV‐2 infection [43].…”

Section: Involvement Of the Complement Cascade In The Immunopathological Phase Of Severe Forms Of Covid‐19mentioning

confidence: 99%

Complement cascade in severe forms of COVID‐19: Recent advances in therapy

2021

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The complement system is an essential component of the innate immune system. The three complement pathways (classical, lectin, alternative) are directly or indirectly activated by the SARS‐CoV‐2 (severe acute respiratory syndrome coronavirus 2). In the most severe forms of COVID‐19, overactivation of the complement system may contribute to the cytokine storm, endothelial inflammation (endotheliitis) and thrombosis. No antiviral drug has yet been shown to be effective in COVID‐19. Therefore, immunotherapies represent a promising therapeutic in the immunopathological phase (following the viral phase) of the disease. Complement blockade, mostly C5a‐C5aR axis blockade, may prevent acute respiratory distress syndrome (ARDS) from worsening or progression to death. Clinical trials are underway.

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Section: Involvement Of the Complement Cascade In The Immunopathological Phase Of Severe Forms Of Covid‐19mentioning

confidence: 99%

Complement cascade in severe forms of COVID‐19: Recent advances in therapy

2021

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“…Evidence suggests that it is likely due to a complex interplay of dysregulated components of both the innate and adaptive immune system upon a background of genetic predisposition 9 . More recent hypothesis states that PG is primarily a T‐cell‐mediated disease, which targets follicular adnexal structures, 10 or a complement pathway‐mediated condition with hyperactivation of C5a, 11 which would explain its correlation with other conditions including hidradenitis suppurativa. Whilst it is classified as a neutrophilic dermatosis and neutrophils predominate in the established histopathology of the disease, it is unclear whether neutrophils are the primary causative cell type in the development of the disease, or otherwise a bystander in established immunological dysfunction, which precipitates the development of PG lesions.…”

Section: Introductionmentioning

confidence: 99%

Pyoderma gangrenosum: A systematic review of the molecular characteristics of disease

Flora

Kozera

Frew

2022

Experimental Dermatology

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Pyoderma gangrenosum is a painful recurrent ulcerative neutrophilic dermatosis in which the pathogenesis is incompletely defined. Current evidence suggests that PG is associated with dysregulation of components of both the innate and adaptive immune system with dysregulation of neutrophil function and contribution of the Th17 immune axis. PG can be present in numerous heterogeneous clinical presentations and be associated with multiple inflammatory conditions including rheumatoid arthritis, inflammatory bowel disease and hidradenitis suppurativa. However, no critical evaluation of the observed molecular characteristics in PG studies in association with their clinical findings has been assessed. Additionally, emerging evidence suggests a potential role for other cell types and immune pathways including B cells, macrophages, autoantibodies and the complement system in PG, although these have not yet been integrated into the pathogenesis of disease. This systematic review aims to critically evaluate the current molecular observations regarding the pathogenesis of PG and discuss associations with clinical characteristics as well as the evidence supporting novel cell types and immune pathways in PG.

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Section: Pathogenesismentioning

confidence: 99%

“…C3a and C5a are strong neutrophil activators and recruiters (Figure 2), suggesting that complement inhibition might be a line of action in HS treatment. 45,46 High blood concentrations of C5a have been found in HS patients compared with healthy subjects, 42 and reduction of nodules and draining dermal tunnels have been observed following C5a inhibition. 47 Interferon-gamma (IFN-γ) is secreted by Th1 cells and activates endothelial cells contributing to the massive infiltration of inflammatory cells perpetuating the immune response (Figure 4).…”

Section: Disease Severity and Outcome Measuresmentioning

confidence: 99%

New perspectives on the treatment of hidradenitis suppurativa

Amat-Samaranch

Agut-Busquet

Vilarrasa

et al. 2021

Therapeutic Advances in Chronic Disease

105

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Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by the presence of painful nodules, abscesses, chronically draining fistulas, and scarring in apocrine gland-bearing areas of the body. The exact pathogenesis of HS is not yet well understood, but there is a consensus in considering HS a multifactorial disease with a genetic predisposition, an inflammatory dysregulation, and an influence of environmental modifying factors. Therapeutic approach of HS is challenging due to the wide clinical manifestations of the disease and the complex pathogenesis. This review describes evidence for effectiveness of current and emerging HS therapies. Topical therapy, systemic treatments, biological agents, surgery, and light therapy have been used for HS with variable results. Adalimumab is the only US Food and Drug Administration (FDA) approved biologic agent for moderate-to-severe HS, but new therapeutic options are being studied, targeting different specific cytokines involved in HS pathogenesis. Comparing treatment outcomes between therapies is difficult due to the lack of randomized controlled trials. Treatment strategy should be selected in concordance to disease severity and requires combination of treatments in most cases.

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Pyoderma gangrenosum: proposed pathogenesis and current use of biologics with an emphasis on complement C5a inhibitor IFX-1

Cited by 21 publications

References 32 publications

Complement cascade in severe forms of COVID‐19: Recent advances in therapy

Complement cascade in severe forms of COVID‐19: Recent advances in therapy

Pyoderma gangrenosum: A systematic review of the molecular characteristics of disease

New perspectives on the treatment of hidradenitis suppurativa

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