Thrombotic thrombocytopenic purpura and defective apoptosis due to CASP8/10 mutations: the role of mycophenolate mofetil

Fioredda, Francesca; Cappelli, Enrico; Mariani, A.; Beccaria, A; Palmisani, Elena; Grossi, Alice; Ceccherini, Isabella; Venè, Roberta; Micalizzi, Concetta; Calvillo, Michaela; Pierri, Filomena; Mancini, Ilaria; Peyvandi, Flora; Corsolini, Fabio; Dufour, Carlo; Miano, Maurizio

doi:10.1182/bloodadvances.2019000575

Cited by 4 publications

(6 citation statements)

References 26 publications

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“…A polygenic mode of inheritance has also been postulated in some cases [15]. This prompted us to develop three different temporarily consecutive next-generation sequencing (NGS)-based gene panels that were used to test patients presenting with complex and/or atypical phenotypes highly suggestive of IEI and yet undiagnosed after testing candidate genes by the traditional Sanger sequencing protocol [45]. Indeed, atypical presentations may be missed when focusing on given phenotypes, and, conversely, larger NGS-based gene panels can lead to identifying variants unseen before and/or in genes whose contribution to a given disease phenotype is not yet completely established [25].…”

Section: Discussionmentioning

confidence: 99%

“…Finding novel variants in a known gene, especially if classified with an uncertain significance, may require additional investigations to prove their association with specific phenotypic patterns [28], that is, more than mere in silico predictions [48,49]. The effect of some variants of the CASP10 and PIK3CD genes, found in patients showing symptoms and laboratory alterations similar to ALPS patients (the so-called ALPS undefined, or ALPS-U), but not fully matching the 2009 NIH revised diagnostic criteria [11], was investigated through proper functional tests, allowing confirmation of their postulated pathogenicity [34,44,45].…”

Section: Discussionmentioning

confidence: 99%

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Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Grossi

Miano

Lanciotti

et al. 2021

Genes

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Inborn errors of immunity (IEI) include a large group of inherited diseases sharing either poor, dysregulated, or absent and/or acquired function in one or more components of the immune system. Next-generation sequencing (NGS) has driven a rapid increase in the recognition of such defects, though the wide heterogeneity of genetically diverse but phenotypically overlapping diseases has often prevented the molecular characterization of the most complex patients. Two hundred and seventy-two patients were submitted to three successive NGS-based gene panels composed of 58, 146, and 312 genes. Along with pathogenic and likely pathogenic causative gene variants, accounting for the corresponding disorders (37/272 patients, 13.6%), a number of either rare (probably) damaging variants in genes unrelated to patients’ phenotype, variants of unknown significance (VUS) in genes consistent with their clinics, or apparently inconsistent benign, likely benign, or VUS variants were also detected. Finally, a remarkable amount of yet unreported variants of unknown significance were also found, often recurring in our dataset. The NGS approach demonstrated an expected IEI diagnostic rate. However, defining the appropriate list of genes for these panels may not be straightforward, and the application of unbiased approaches should be taken into consideration, especially when patients show atypical clinical pictures.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Grossi

Miano

Lanciotti

et al. 2021

Genes

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“…Alternative immunosuppressive therapies: in patients with contraindications to steroids or with refractory disease, cyclosporine A can be effective [ 19 , 163 ]. Mycophenolate mofetil has also been used with success in some case reports [ 164 , 165 ]. Prior to the use of rituximab, vincristine was used for refractory disease, but this is no longer preferred [ 166 ].…”

Section: Acute Managementmentioning

confidence: 99%

Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management

Sukumar

Lämmle

Cataland

2021

JCM

108

132

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Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and ischemic end organ injury due to microvascular platelet-rich thrombi. TTP results from a severe deficiency of the specific von Willebrand factor (VWF)-cleaving protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). ADAMTS13 deficiency is most commonly acquired due to anti-ADAMTS13 autoantibodies. It can also be inherited in the congenital form as a result of biallelic mutations in the ADAMTS13 gene. In adults, the condition is most often immune-mediated (iTTP) whereas congenital TTP (cTTP) is often detected in childhood or during pregnancy. iTTP occurs more often in women and is potentially lethal without prompt recognition and treatment. Front-line therapy includes daily plasma exchange with fresh frozen plasma replacement and immunosuppression with corticosteroids. Immunosuppression targeting ADAMTS13 autoantibodies with the humanized anti-CD20 monoclonal antibody rituximab is frequently added to the initial therapy. If available, anti-VWF therapy with caplacizumab is also added to the front-line setting. While it is hypothesized that refractory TTP will be less common in the era of caplacizumab, in relapsed or refractory cases cyclosporine A, N-acetylcysteine, bortezomib, cyclophosphamide, vincristine, or splenectomy can be considered. Novel agents, such as recombinant ADAMTS13, are also currently under investigation and show promise for the treatment of TTP. Long-term follow-up after the acute episode is critical to monitor for relapse and to diagnose and manage chronic sequelae of this disease.

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“…Mycophenolate Mofetil (MMF): Use in TTP is anecdotal, [79][80][81][82][83][84] although it is widely used in other autoimmune conditions such as SLE. 85,86 Ciclosporin: A randomised controlled study compared with steroids was stopped because of improved ADAMTS13 recovery in the steroid group. 87 Azathioprine: There are few publications in iTTP, 88,89 but it may be useful in pregnancy and breastfeeding.…”

Section: Additional Immunosuppressive Therapiesmentioning

confidence: 99%

A British Society for Haematology Guideline: Diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies

Scully,

Rayment,

Clark

et al. 2023

Br J Haematol

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SummaryThe objective of this guideline is to provide healthcare professionals with clear, up‐to‐date and practical guidance on the management of thrombotic thrombocytopenic purpura (TTP) and related thrombotic microangiopathies (TMAs), including complement‐mediated haemolytic uraemic syndrome (CM HUS); these are defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Within England, all TTP cases should be managed within designated regional centres as per NHSE commissioning for highly specialised services.

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Thrombotic thrombocytopenic purpura and defective apoptosis due to CASP8/10 mutations: the role of mycophenolate mofetil

Abstract: Key Points Immunological dysregulation may underlie unusual autoimmune diseases, which also deserve to be investigated from a genetic point of view.

Cited by 4 publications

References 26 publications

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management

A British Society for Haematology Guideline: Diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies

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