Thrombotic microangiopathy induced by interferon beta in patients with multiple sclerosis: three cases treated with eculizumab

Allinovi, Marco; Cirami, Calogero; Caroti, Leonardo; Antognoli, Giulia; Farsetti, Silvia; Amato, Maria Pia; Minetti, Enrico

doi:10.1093/ckj/sfw143

Cited by 26 publications

(30 citation statements)

References 31 publications

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“…Also, anifrolumab is a monoclonal antibody against the type I interferon receptor that inhibits the activity of all type I interferons and is being tested in patients with systemic lupus erythematosus. 51 Our data suggest studying these therapies in patients with TA-TMA may benefit other thrombotic microangiopathies, especially in those with refractory disease.…”

Section: Discussionmentioning

confidence: 78%

Interferon-complement loop in transplant-associated thrombotic microangiopathy

et al. 2020

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Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.

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Section: Discussionmentioning

confidence: 78%

Interferon-complement loop in transplant-associated thrombotic microangiopathy

et al. 2020

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“…We observed a high incidence of clinically significant complement-mediated thrombotic microangiopathy (TMA) associated with multi-organ injury in children and young adults with a diagnosis of HLH. TMA has not been previously associated with interferon gamma-driven diseases like HLH [26], but TMA has been reported as an iatrogenic therapylimiting side effect in patients receiving interferon alpha and beta therapy [27][28][29][30][31]. We hypothesized that high levels of interferon gamma in HLH might contribute directly to endothelial damage or injure endothelium through complement system activation.…”

Section: Discussionmentioning

confidence: 99%

Thinking Beyond HLH: Clinical Features of Patients with Concurrent Presentation of Hemophagocytic Lymphohistiocytosis and Thrombotic Microangiopathy

et al. 2020

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Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation driven mainly by high levels of interferon gamma. The clinical presentation of HLH can have considerable overlap with other inflammatory conditions. We present a cohort of patients with therapy refractory HLH referred to our center who were found to have a simultaneous presentation of complement-mediated thrombotic microangiopathy (TMA). Twenty-three patients had therapy refractory HLH (13 primary, 4 EVB-HLH, 6 HLH without known trigger). Sixteen (69.6%) met high-risk TMA criteria. Renal failure requiring renal replacement therapy, severe hypertension, serositis, and gastrointestinal bleeding were documented only in patients with HLH who had concomitant complement-mediated TMA. Patients with HLH and without TMA required ventilator support mainly due to CNS symptoms, while those with HLH and TMA had respiratory failure predominantly associated with pulmonary hypertension, a known presentation of pulmonary TMA. Ten patients received eculizumab for complement-mediated TMA management while being treated for HLH. All patients who received the complement blocker eculizumab in addition to the interferon gamma blocker emapalumab had complete resolution of their TMA and survived. Our observations suggest coactivation of both interferon and complement pathways as a potential culprit in the evolution of thrombotic microangiopathy in patients with inflammatory disorders like refractory HLH and may offer novel therapeutic approaches for these critically ill patients. TMA should be considered in children with HLH and multi-organ failure, as an early institution of a brief course of complement blocking therapy in addition to HLH-targeted therapy may improve clinical outcomes in these patients.

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“…Further studies confirm that TMA is a severe complication of IFN-beta RRMS treatment. Lately, five patients were reported to have IFN-induced TMA following long-term treatment (78)(79)(80). Interestingly, renal function of three patients improved only after administration of eculizumab, (80).…”

Section: Neurologymentioning

confidence: 99%

“…Lately, five patients were reported to have IFN-induced TMA following long-term treatment (78)(79)(80). Interestingly, renal function of three patients improved only after administration of eculizumab, (80). Clinical translation of those studies raises awareness of neurologists for early recognition and management of TMA when prescribing DMTs.…”

Section: Neurologymentioning

confidence: 99%

“…In true DITMA, plasma exchange is ineffective (85). On the other hand, numerous reports have now confirmed that complement inhibition with eculizumab shows efficacy in DITMA (22,26,44,45,50,63,80). Eculizumab is a first-inclass monoclonal antibody that blocks terminal complement activation with proven safety and efficacy in complementmediated TMAs (86).…”

Section: Therapeutic Potentialsmentioning

confidence: 99%

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