In the past few years, the spectrum of monogenic systemic auto‐inflammatory diseases (MSAID) has widely expanded beyond the typical recurrent fever. Immuno‐haematological features, as cytopenias, ...hypogammaglobulinemia, hypereosinophilia, lymphoproliferation and immunodeficiency, have been described in association of several MSAID. The objective of this review was to describe these particular MSAID. MSAID must be suspected in front of immuno‐haematological features associated with non‐infectious recurrent fever, chronic systemic inflammation, inflammatory cutaneous manifestations, arthritis or inflammatory bowel disease. Genes and cellular mechanisms involved are various but some of them are of special interest. Defects in actine regulation pathway are notably associated with cytopenia and immune deficiency. Because of their frequency, ADA2 deficiency and Vacuoles, E1‐Enzyme, X‐linked, auto‐inflammatory, Somatic (VEXAS) syndrome deserve to be noticed. ADA2 deficiency results in polyarteritis nodosa‐like presentation with a wide panel of manifestations including cytopenia(s), lymphoproliferation and immune deficiency. Neutrophilic dermatosis or chondritis associated with macrocytic anaemia or myelodysplasia should lead to screen for VEXAS. Of note, most of MSAID are associated with inflammatory anaemia. We proposed here a clinical and pragmatic approach of MSAID associated with immuno‐haematological features.
In the past few years, the spectrum of monogenic systemic auto‐inflammatory diseases has widely expanded beyond the typical recurrent fever. Immuno‐haematological features, as cytopenias, hypogammaglobulinemia, hypereosinophilia, lymphoproliferation and immunodeficiency, have been described in association of several MSAID. We proposed here a clinical and pragmatic approach of MSAID associated with immuno‐haematological features.
Infections and AA amyloidosis: An overview Deshayes, Samuel; Aouba, Achille; Grateau, Gilles ...
International journal of clinical practice (Esher),
June 2021, 2021-Jun, 2021-06-00, 20210601, 2021-06, Volume:
75, Issue:
6
Journal Article
Peer reviewed
Open access
Background
Amyloidoses are a heterogeneous group of systemic diseases characterised by extracellular accumulation of insoluble amyloid fibrils derived from unfolded proteins. Inflammatory (AA) ...amyloidosis can complicate various inflammatory disorders that are associated with a sustained acute phase response and serum amyloid A (SAA) protein overproduction. Chronic infections were the first recognised cause of amyloidoses. However, with the better management of underlying diseases, the frequency of AA amyloidosis is decreasing.
Purpose
The aim of this overview was to discuss the several infections associated with AA amyloidosis and the relative frequency of infections as aetiological factors.
Methods
A search of the literature was performed using the PubMed database using the MeSH terms “Amyloidosis” and “Infections,” from inception to December 31st, 2019. Articles written in other languages than English or French were excluded.
Results
The frequency of AA amyloidosis secondary to infections decreased from more than 50% to less than 20% after the 2000s, with a parallel increase in the frequency of AA amyloidosis secondary to inflammatory diseases and to an unknown cause.
Conclusion
Whereas new antibiotics have been developed and sanitary conditions are better, infections still represent 5%‐30% of the causes of AA amyloidosis, including in developed countries. These data argue for better screening of chronic infections to prevent AA amyloidosis and the development of new strategies to manage recurrent infections.
Summary
Azacitidine can be effective in myelodysplastic syndromes (MDS) associated with inflammatory/autoimmune diseases. Vacuoles, E1 Enzyme, X‐linked, Autoinflammatory, Somatic syndrome (VEXAS) is ...a new monogenic autoinflammatory syndrome caused by somatic ubiquitin‐like modifier‐activating enzyme 1 (UBA1) mutation, often associated with MDS, whose treatment is difficult and not yet codified. Based on a French nationwide registry of 116 patients with VEXAS, we report the efficacy and safety of azacitidine treatment in 11 patients with VEXAS with MDS. Clinical response of VEXAS to azacitidine was achieved in five patients (46%), during 6, 8+, 12, 21, 27+ months respectively, suggesting that azacitidine can be effective in selected patients with VEXAS and associated MDS.
Summary Background Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits ...KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments. Methods In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18–75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8–24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , number NCT00814073. Findings Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses weighted generalised estimating equation) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2–10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight 11% of 70 in the masitinib group vs one 2% of 63 in the placebo group), rash (four 6% vs none), and asthenia (four 6% vs one 2%). The most frequent serious adverse events were diarrhoea (three patients 4% vs one 2%) and urticaria (two 3% vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). Interpretation These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. Funding AB Science (Paris, France).
Mast cells and basophils are best known for their key role during allergic responses 1. Yet, they also have pivotal functions in innate and acquired (via IgE) defense mechanisms against microbes and ...parasites as well as in the neutralization of certain toxins such as snake venoms, through the release of proteases and other mediators contained in their cytoplasmic granules 2, 3 (Figure 1, example of a mast cell releasing cytoplasmic granules stained using fluorochrome‐labeled avidin, red). Recent work indicates that these cells have also important functions in a much broader range of inflammatory and pathological conditions including autoimmune diseases, cardiovascular diseases, skin diseases, neuroinflammatory disease and even cancer. However, the mechanisms by which mast cells and basophils mediate their functions in these settings remain largely unknown. Not surprisingly, these new aspects of mast cell and basophil biology have raised interest in the immunology community, with the emergence of new groups focused on studying their involvement in the maintenance of homeostasis and the promotion of disease.
AA amyloidosis associated with Fabry disease Terré, Alexandre; Knebelmann, Bertrand; Buob, David ...
International journal of clinical practice (Esher),
October 2020, 2020-Oct, 2020-10-00, 20201001, 2020-10, Volume:
74, Issue:
10
Journal Article
Peer reviewed
Open access
Background
Fabry disease (FD) is the second most common lysosomal storage disorder, carrying a large morbidity and mortality. It has been recently reported that lysosomal storage disorders could ...cause inflammation and, subsequently, AA amyloidosis (AAA). Our aim was to describe AAA cases occurring in the course of FD.
Patients and Methods
We described two patients displaying both AAA and FD and an additional case from the literature.
Results
Three female patients originating from Europe (n = 2) and Algeria (n = 1) harboured heterozygous GLA mutations. The median age at AAA diagnosis was 61 years old. The diagnosis of Fabry was made before the diagnosis of AAA (n = 1) or concomitantly (n = 2). At AAA diagnosis, two patients displayed a nephrotic syndrome; all had inflammation.
Conclusion
Fabry disease can be associated with AAA, suggesting that an inflammatory component could exist in this genetic disease.
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