Biallelic mutations in the CFHR genes underlying atypical hemolytic uremic syndrome in a patient with catastrophic adult-onset Still&apos;s disease and recurrent macrophage activation syndrome: A case report.

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Abstract

We report the fatal case of a 20-year-old woman with refractory adult-onset Still's disease (AOSD) accompanied by fulminant macrophage activation syndrome (MAS) and atypical hemolytic uremic syndrome (aHUS). Anakinra and tocilizumab temporarily controlled AOSD. In 2021, she presented to ICU with generalized tonic-clonic seizure, lymphocytic aseptic meningitis, and acute kidney injury. Despite hemodialysis and methylprednisolone, she developed another seizure, MAS, and disseminated intravascular coagulation (DIC). Following brief control, MAS flares -reflected by increased plasma CXCL9 and CXCL10- re-emerged and were controlled through dexamethasone, etoposide, cyclosporin and tofacitinib. No mutations were detected in haemophagocytic lymphohistiocytosis (HLH)-associated genes, nor in genes associated with periodic fever syndromes. Post-mortem genetic testing revealed loss-of-function biallelic deletions in complement factor H-related proteins (CFHR) genes, predisposing aHUS. This case underscores the importance of prompt genetic assessment of complement-encoding alleles, in addition to HLH-related genes, in patients with severe AOSD with recurrent MAS and features of thrombotic microangiopathy (TMA).

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Preliminary criteria for classification of adult Still's disease.

H Kashiwagi, Yoshitaka Matsumoto, M Yamaguchi … (1992)

We have attempted to design classification criteria for adult Still's disease by analyzing the data obtained through a multicenter survey of 90 Japanese patients with this disease and of 267 control patients. The proposed criteria consisted of fever, arthralgia, typical rash, and leukocytosis as major, and sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and the absence of rheumatoid factor and antinuclear antibody as minor criteria. Requiring 5 or more criteria including 2 or more major criteria yielded 96.2% sensitivity and 92.1% specificity. However, an exclusion process will be needed for an accurate classification, since this disease is relatively rare.

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How I treat hemophagocytic lymphohistiocytosis.

Michael B Jordan, Carl E Allen, Sheila Weitzman … (2011)

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, occurring as either a familial disorder or a sporadic condition, in association with a variety of triggers. This immune dysregulatory disorder is prominently associated with cytopenias and a unique combination of clinical signs and symptoms of extreme inflammation. Prompt initiation of immunochemotherapy is essential for survival, but timely diagnosis may be challenging because of the rarity of HLH, its variable presentation, and the time required to perform diagnostic testing. Therapy is complicated by dynamic clinical course, high risk of treatment-related morbidity, and disease recurrence. Here, we review the clinical manifestations and patterns of HLH and describe our approach to the diagnosis and therapy for this elusive and potentially lethal condition.

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A comprehensive review on adult onset Still's disease

Piero Ruscitti, Yehuda Shoenfeld, Roberto Giacomelli (2018)

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown etiology usually affecting young adults; spiking fever, arthritis and evanescent rash are commonly observed during the disease. Other frequently observed clinical features include sore throat, hepatomegaly, splenomegaly, lymphadenopathy and serositis. Furthermore, AOSD patients may experience different life-threating complications. Macrophage activation syndrome (MAS) has been reported up to 15% of AOSD patients and it is considered to be the most severe complication of the disease being characterised by high mortality rate. During AOSD, laboratory tests reflect the systemic inflammatory process showing high levels of erythrocyte sedimentation rate and C-reactive protein. In addition, the ferritin levels are typically higher than those observed in other autoimmune, inflammatory, infectious, or neoplastic diseases. Analysing AOSD disease course, 3 different clinical patterns of AOSD have been identified: i. monocyclic pattern, characterised by a systemic single episode; ii. polycyclic pattern, characterised by multiple, ≤ 1 year lasting, flares, alternating with remissions; iii. chronic pattern, related to a persistently active disease with associated polyarthritis. At present, AOSD therapeutic strategy is aimed at targeting pro-inflammatory signs and symptoms, preventing organ damage and life-threating complications and minimising adverse effects of treatment. However, the treatment of AOSD remains largely empirical, lacking controlled clinical trials. High dosages of corticosteroids are usually the first line therapy when the systemic symptoms predominate. Despite this treatment, a large percentage of patients experiences several flares with an evolution toward the chronic disease course and up to 16% of patients die during the follow up, due to AOSD-related complications. On these bases, in the last years, biological agents have been successfully used in refractory cases. Finally, multiple recent lines of evidence have suggested new insights in AOSD pathogenesis unmasking further therapeutic targets. In fact, small molecules, used in experimental MAS models, might represent new therapeutic options.

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Author and article information

Journal

Journal ID (iso-abbrev): Clin Immunol

Title: Clinical immunology (Orlando, Fla.)

Publisher: Elsevier BV

ISSN (Electronic): 1521-7035

ISSN (Print): 1521-6616

Publication date (Electronic): Dec 2023

Volume: 257

Affiliations

[1 ] Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Belgium.

[2 ] Laboratory of Cardiology, Department of Cardiovascular Sciences, KU Leuven, Belgium; Department of Cardiovascular Diseases, University Hospitals Leuven, Belgium.

[3 ] Laboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium; European Reference Network for Immunodeficiency, Autoinflammatory, Autoimmune and Pediatric Rheumatic disease (ERN-RITA), University Hospitals Leuven, Belgium.

[4 ] Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Belgium.

[5 ] European Reference Network for Immunodeficiency, Autoinflammatory, Autoimmune and Pediatric Rheumatic disease (ERN-RITA), University Hospitals Leuven, Belgium; Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Belgium; Department of Pediatric Rheumatology, University Hospitals Leuven, Belgium.

[6 ] Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Belgium.

[7 ] Department of Human Genetics, KU Leuven, Belgium.

[8 ] Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Belgium.

[9 ] Laboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium; Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Belgium.

[10 ] Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Belgium. Electronic address: paul.proost@kuleuven.be.

[11 ] European Reference Network for Immunodeficiency, Autoinflammatory, Autoimmune and Pediatric Rheumatic disease (ERN-RITA), University Hospitals Leuven, Belgium; Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Belgium.