Dramatic effects of eculizumab in a child with diffuse proliferative lupus nephritis resistant to conventional therapy

Coppo, Rosanna; Peruzzi, Licia; Amore, Alessandro; Martino, Silvana; Vergano, Luca; Lastauka, Inna; Schieppati, Arrigo; Noris, Marina; Tovo, Pier-Angelo; Remuzzi, Giuseppe

doi:10.1007/s00467-014-2944-y

Cited by 68 publications

(42 citation statements)

References 14 publications

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“…*P≤0.05, **P≤0.01 (Student's t-test). (Coppo et al, 2015) and even asthma (Smith et al, 2012). Interestingly, the administration of anti-complement antibodies not only prevents host cell lysis, but also reduces inflammatory markers in these patients (Weitz et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Complement-mediated ‘bystander’ damage initiates host NLRP3 inflammasome activation

Suresh

Chandrasekaran

Sutterwala

et al. 2016

Journal of Cell Science

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Complement activation has long been associated with inflammation, primarily due to the elaboration of the complement anaphylotoxins C5a and C3a. In this work, we demonstrate that the phagocytosis of complement-opsonized particles promotes host inflammatory responses by a new mechanism that depends on the terminal complement components (C5b-C9). We demonstrate that during the phagocytosis of complement-opsonized particles, the membrane attack complex (MAC) of complement can be transferred from the activating particle to the macrophage plasma membrane by a 'bystander' mechanism. This MAC-mediated bystander damage initiates NLRP3 inflammasome activation, resulting in caspase-1 activation and IL-1β and IL-18 secretion. Inflammasome activation is not induced when macrophages phagocytize unopsonized particles or particles opsonized with serum deficient in one of the terminal complement components. The secretion of IL-1β and IL-18 by macrophages depends on NLRP3, ASC (also known as PYCARD) and caspase-1, as macrophages deficient in any one of these components fail to secrete these cytokines following phagocytosis. The phagocytosis of complement-opsonized particles increases leukocyte recruitment and promotes T helper 17 cell (T H 17) biasing. These findings reveal a new mechanism by which complement promotes inflammation and regulates innate and adaptive immunity.

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Section: Discussionmentioning

confidence: 99%

Complement-mediated ‘bystander’ damage initiates host NLRP3 inflammasome activation

Suresh

Chandrasekaran

Sutterwala

et al. 2016

Journal of Cell Science

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“…The data suggest that the more rapid the initiation of therapy with eculizumab is, the greater the improvements in renal function; preferably within 1 week after disease onset [25]. Consequently, in a patient responding poorly to PEX therapy, eculizumab might be initiated [26][27][28][29][30][31][32]. In cases where diagnosis of aHUS is known at the time of acute presentation (previous mutation studies), first-line therapy with eculizumab should be considered in place of PEX [19,21].…”

Section: Discussionmentioning

confidence: 99%

Two cases of atypical hemolytic uremic syndrome (aHUS) and eosinophilic granulomatosis with polyangiitis (EGPA): a possible relationship

et al. 2017

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“…As expected, complement inhibition is effective in patients who have a mutation in complement molecules or autoantibodies against factor H. The efficacy of therapeutic complement inhibition in patients with secondary HUS has not been systematically assessed, but it has been shown to be beneficial in a number of patients who do not have a mutation in any of the studied complement proteins. 117 These include patients with autoimmunity (eg, scleroderma), 118 systemic lupus erythematosus, 119,120 or catastrophic antiphospholipid syndrome 121,122 and secondary HUS associated with postpartum period, 123 HIV infection, 124 use of cytotoxic drugs, 35 and either bone marrow or solid organ transplantation. 27,28 On the basis of these multiple single cases, it seems that complement is involved in at least some patients with secondary HUS.…”

Section: Therapeutic Complement Inhibition Provides Insight Into Pathmentioning

confidence: 99%

HUS and atypical HUS

Jokiranta

2017

Blood

240

260

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Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. HUS is usually categorized as typical, caused by Shiga toxin–producing Escherichia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Among the 30% to 50% of patients with HUS who have no detectable complement defect, some have either impaired diacylglycerol kinase ε (DGKε) activity, cobalamin C deficiency, or plasminogen deficiency. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In this review, the differences and similarities in the pathogenesis of STEC-HUS, aHUS, and secondary HUS are discussed. Common for the pathogenesis seems to be the vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis. This process can be stopped by therapeutic complement inhibition in most patients with aHUS, but usually not those with a DGKε mutation, and some patients with STEC-HUS or secondary HUS. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice.

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Dramatic effects of eculizumab in a child with diffuse proliferative lupus nephritis resistant to conventional therapy

Abstract: C5 inhibition by eculizumab completely reversed clinical symptoms and laboratory renal signs of severe lupus nephritis. Blocking complement-system activation with the use of targeted drugs may be a new and exciting strategy to treat SLE patients unresponsive to conventional therapy.

Cited by 68 publications

References 14 publications

Complement-mediated ‘bystander’ damage initiates host NLRP3 inflammasome activation

Complement-mediated ‘bystander’ damage initiates host NLRP3 inflammasome activation

Two cases of atypical hemolytic uremic syndrome (aHUS) and eosinophilic granulomatosis with polyangiitis (EGPA): a possible relationship

HUS and atypical HUS

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