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Pediatric Rheumatology Online Journal Oct 2022Systemic autoinflammatory diseases (SAIDs) are hyperinflammatory and immune-dysregulation conditions that present in childhood. This kind of disease is a rare disease... (Review)
Review
BACKGROUND
Systemic autoinflammatory diseases (SAIDs) are hyperinflammatory and immune-dysregulation conditions that present in childhood. This kind of disease is a rare disease with early-onset, severe condition and difficult diagnosis, which seriously affects the growth and development of children. Most children need a genetic diagnosis. However, with the limitation of access to genetic testing and the detection of somatic mutations, the diagnosis of SAIDs remains challenging. IL-1 is one of the important cytokines involved in the pathogenesis of SAIDs. Here we briefly review monogenic SAIDs mediated by aberrant IL-1 production, with the aim to further understand the pathogenesis, clinical manifestations and treatments of IL-1 mediated SAIDs.
METHODS
Literature reviews were performed using "PubMed" and "Web of Science" by searching for the terms "autoinflammatory diseases" and "IL-1".
RESULTS
Monogenic SAIDs mediated by IL-1 include MKD, FMF, TRAPS, PAAND, PAPA, CAPS, DIRA, Majeed syndrome, NAIAD, NLRC4-MAS, PFIT, APLAID. Monogenic SAIDs have early onset, various clinical manifestations and difficult diagnosis, so early recognition and early treatment can reduce the complications and enhance the quality of life.
CONCLUSIONS
There are many kinds of IL-1 mediated SAIDs. Pediatricians should be alert to SAIDs in the face of the patients with repeated fever, repeated rash and poor effect of routine treatment. The patients should be carried out with gene testing and treatment in time.
Topics: Animals; Child; Cytokines; Genetic Testing; Hereditary Autoinflammatory Diseases; Humans; Quality of Life; Simian Acquired Immunodeficiency Syndrome
PubMed: 36253853
DOI: 10.1186/s12969-022-00728-0 -
Current Opinion in Rheumatology Sep 2013To provide an update on the genetics and immunologic basis of autoinflammatory bone disorders including chronic recurrent multifocal osteomyelitis including the... (Review)
Review
PURPOSE OF REVIEW
To provide an update on the genetics and immunologic basis of autoinflammatory bone disorders including chronic recurrent multifocal osteomyelitis including the monogenic forms of the disease.
RECENT FINDINGS
Ongoing research in murine, canine and human models of sterile bone inflammation has solidified the hypothesis that sterile bone inflammation can be genetically driven. Mutations in Pstpip2, LPIN2 and IL1RN have been identified in monogenic autoinflammatory bone disorders that have allowed more detailed dissection of the immunologic defects that can produce sterile osteomyelitis. Recent studies in murine chronic multifocal osteomyelitis, deficiency of the interleukin-1 receptor antagonist (DIRA), Majeed syndrome and SAPHO syndrome reveal abnormalities in innate immune system function. IL-1 pathway dysregulation is present in several of these disorders and blocking IL-1 therapeutically has resulted in control of disease in DIRA, Majeed syndrome and in some cases of SAPHO and CRMO. Basic research demonstrates the importance of the innate immune system in disease pathogenesis and offers clues about potential disease triggers.
SUMMARY
Research and clinical data produced over the last several years support the important role of innate immunity in sterile osteomyelitis. Based on what has been learned in the monogenic autoinflammatory bone disorders, IL-1 is emerging as an important pathway in the development of sterile bone inflammation.
Topics: Acquired Hyperostosis Syndrome; Anemia, Dyserythropoietic, Congenital; Animals; Chronic Disease; Disease Models, Animal; Dogs; Gram-Positive Bacterial Infections; Hereditary Autoinflammatory Diseases; Humans; Immunity, Innate; Immunologic Deficiency Syndromes; Interleukin-1; Mice; Osteomyelitis; Propionibacterium acnes; Recurrence; Tumor Necrosis Factor-alpha
PubMed: 23917160
DOI: 10.1097/BOR.0b013e328363eb08 -
The Journal of Rheumatology Jun 2016
Topics: Adolescent; Anemia, Dyserythropoietic, Congenital; Arthritis, Juvenile; Diphosphonates; Follow-Up Studies; Genetic Predisposition to Disease; Genetic Variation; Homozygote; Humans; Immunologic Deficiency Syndromes; Magnetic Resonance Imaging; Male; Methotrexate; Mutation; Nuclear Proteins; Osteomyelitis; Pamidronate; Pedigree; Phenotype; Positron-Emission Tomography
PubMed: 27252506
DOI: 10.3899/jrheum.151193 -
Monogenic autoinflammatory syndromes: state of the art on genetic, clinical, and therapeutic issues.International Journal of Rheumatology 2013Monogenic autoinflammatory syndromes (MAISs) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and... (Review)
Review
Monogenic autoinflammatory syndromes (MAISs) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and involvement of skin, serous membranes, eyes, joints, gastrointestinal tract, and nervous system, predominantly with a childhood onset. To date, there are twelve known MAISs: familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, familial cold urticaria syndrome, Muckle-Wells syndrome, CINCA syndrome, mevalonate kinase deficiency, NLRP12-associated autoinflammatory disorder, Blau syndrome, early-onset sarcoidosis, PAPA syndrome, Majeed syndrome, and deficiency of the interleukin-1 receptor antagonist. Each of these conditions may manifest itself with more or less severe inflammatory symptoms of variable duration and frequency, associated with findings of increased inflammatory parameters in laboratory investigation. The purpose of this paper is to describe the main genetic, clinical, and therapeutic aspects of MAISs and their most recent classification with the ultimate goal of increasing awareness of autoinflammation among various internal medicine specialists.
PubMed: 24282415
DOI: 10.1155/2013/513782 -
European Review For Medical and... Mar 2018Chronic recurrent multifocal osteomyelitis (CRMO) is a sporadic condition of inflammatory bone pain that occurs as recurrent flares because of osteomyelitis, which...
Chronic recurrent multifocal osteomyelitis (CRMO) is a sporadic condition of inflammatory bone pain that occurs as recurrent flares because of osteomyelitis, which presents in the form of multiple aseptic foci. The estimated prevalence of CRMO is 1-2 per million, affecting mostly children, in the age group of 2 to 17. Main symptoms of CRMO are bone inflammation and pain, which are generally worse at night. Other symptoms seen on radiographs indicate osteolytic lesions surrounded by sclerosis, at later stages of the disease. Markers of inflammation, viz. tumor necrosis factor a and C-reactive protein are elevated in many cases. Because of similar symptoms, differential diagnosis is needed to confirm CRMO from infectious osteomyelitis, bone tumors, and other diseases. The genetic component is likely in some cases such as Majeed syndrome, deficiency of IL-1 antagonist, etc. Imaging is the essential part of diagnosing CRMO, and magnetic resonance imaging of the whole body is the most widely used and recommended method for the evaluation of multiple foci, as compared to radiography for reasons of sensitivity as well as prevention of excessive exposure of affected children to radiation. CRMO is considered an autoimmune and auto-inflammatory disorder, but its precise pathophysiology is not clear. Current treatment options are non-steroid anti-inflammatory drugs like naproxen, as the primary choice, and the bisphosphonates such as pamidronate as the second choice, to counter the symptoms and to reduce bone lesions. The surgical option is the choice for recalcitrant cases, even though recurrence may still be a problem.
Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Bone and Bones; C-Reactive Protein; Child; Child, Preschool; Diagnosis, Differential; Diphosphonates; Female; Humans; Inflammation; Magnetic Resonance Imaging; Male; Naproxen; Osteomyelitis; Tumor Necrosis Factor-alpha
PubMed: 29565497
DOI: 10.26355/eurrev_201803_14482 -
Annals of the Rheumatic Diseases Mar 2013Majeed syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a...
BACKGROUND AND OBJECTIVE
Majeed syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a neutrophilic dermatosis that is caused by mutations in LPIN2. Long-term outcome is poor. This is the first report detailing the treatment of Majeed syndrome with biological agents and demonstrates clinical improvement with IL-1blockade.
METHODS
We describe the clinical presentation, genetic analysis, cytokine profiles and response to biological therapy in two brothers with Majeed syndrome.
RESULTS
Both boys were homozygous for a novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X), confirming the diagnosis. Their bone disease and anaemia were refractory to treatment with corticosteroids. Both siblings had elevated proinflammatory cytokines in their serum, including tumour necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no improvement. IL-1 inhibition with either a recombinant IL-1 receptor antagonist (anakinra) or an anti-IL-1β antibody (canakinumab) resulted in dramatic clinical and laboratory improvement.
CONCLUSIONS
The differential response to treatment with TNF-α or IL-1 blocking agents sheds light into disease pathogenesis; it supports the hypothesis that Majeed syndrome is an IL-1β dependent autoinflammatory disorder, and further underscores the importance of IL-1 in sterile bone inflammation.
Topics: Anemia, Dyserythropoietic, Congenital; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Base Sequence; Child, Preschool; Cytokines; Humans; Immunologic Deficiency Syndromes; Infant; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Male; Nuclear Proteins; Osteomyelitis; Siblings
PubMed: 23087183
DOI: 10.1136/annrheumdis-2012-201818 -
Archives of Rheumatology Sep 2019Majeed syndrome (MS) is a rare, autosomal recessive, autoinflammatory disease characterized by recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia,...
Majeed syndrome (MS) is a rare, autosomal recessive, autoinflammatory disease characterized by recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and inflammatory dermatome. In this article, we report the cases of two siblings with MS. Genetic studies of both siblings were obtained and revealed mutations in LPIN2 gene by means of a homozygous single-base pair change in the donor splice site of exon 17 (c.2327+1G>C). Both patients underwent different modalities of treatment for MS which involved immune-suppressive and biologic therapies. We observed a significant clinical response to biologic anti-interleukin-1 (IL-1) therapy in our patients. This impressive clinical response indicates the pivotal role of IL-1 in MS pathogenesis. There are limited data on the use of anti-IL-1 therapy in treating MS due to the rarity of the condition. Anti-IL-1 therapy should be considered as a promising treatment for this disease.
PubMed: 31598604
DOI: 10.5606/ArchRheumatol.2019.7267 -
The Journal of Experimental Medicine Feb 2017Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1β or its...
Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1β or its receptor. However the role of lipin-2 during IL-1β production remains elusive. We show here that lipin-2 controls excessive IL-1β formation in primary human and mouse macrophages by several mechanisms, including activation of the inflammasome NLRP3. Lipin-2 regulates MAPK activation, which mediates synthesis of pro-IL-1β during inflammasome priming. Lipin-2 also inhibits the activation and sensitization of the purinergic receptor P2X7 and K efflux, apoptosis-associated speck-like protein with a CARD domain oligomerization, and caspase-1 processing, key events during inflammasome activation. Reduced levels of lipin-2 in macrophages lead to a decrease in cellular cholesterol levels. In fact, restoration of cholesterol concentrations in cells lacking lipin-2 decreases ion currents through the P2X7 receptor, and downstream events that drive IL-1β production. Furthermore, lipin-2-deficient mice exhibit increased sensitivity to high lipopolysaccharide doses. Collectively, our results unveil lipin-2 as a critical player in the negative regulation of NLRP3 inflammasome.
Topics: Animals; Caspase 1; Cells, Cultured; Cholesterol; Extracellular Signal-Regulated MAP Kinases; Interleukin-1beta; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphatidate Phosphatase; Potassium; Receptors, Purinergic P2X7; Signal Transduction; Toll-Like Receptor 4
PubMed: 28031477
DOI: 10.1084/jem.20161452 -
Indian Journal of Orthopaedics 2018Chronic recurrent multifocal osteomyelitis (CRMO) is a rare auto-inflammatory disease of the bone. It tends to be multifocal and usually the symptoms tend to run for...
BACKGROUND
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare auto-inflammatory disease of the bone. It tends to be multifocal and usually the symptoms tend to run for months and years before diagnosis is usually made. The objective of our study was to understand the clinical presentation and short-term response to treatment of CRMO patients.
MATERIALS AND METHODS
A retrospective analysis of patients diagnosed with CRMO between 2011 and 2016 was done. Case records of these were retrospectively reviewed for clinical features, investigations and treatment received.
RESULTS
Six patients were diagnosed with CRMO. The median age of onset and time to diagnosis from onset of symptoms was 8 and 3.5 years respectively. Lower limb bones were the most commonly involved.
CONCLUSIONS
There is significant delay in diagnosis of CRMO and this could be because of a lack of awareness of this condition amongst clinicians. Our case series with only male affection is rather unique as compared to other case series reported in medical literature which tend to have more female predilection. Pain with or without swelling was the most common symptom. Most of patients responded to combination therapy.
PubMed: 30532310
DOI: 10.4103/ortho.IJOrtho_464_17 -
Arthritis and Rheumatism Mar 2007Majeed syndrome is an autoinflammatory disorder consisting of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic...
Majeed syndrome is an autoinflammatory disorder consisting of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis. To date, 2 unrelated families with Majeed syndrome have been reported. Mutations in LPIN2 have been found in both families. Here we report a third consanguineous family with Majeed syndrome with a novel mutation. The patient, a 3-year-old Arabic girl, had hepatosplenomegaly and anemia as a neonate. At age 15 months, she developed recurrent episodes of fever and multifocal osteomyelitis. In addition, bone marrow aspiration demonstrated significant dyserythropoiesis, suggesting Majeed syndrome. Coding sequences and splice sites of LPIN2 were sequenced in the patient and her mother. A homozygous single-basepair change was detected in the donor splice site of exon 17 (c.2327+1G>C) in the patient; her mother was heterozygous at this site. These data confirm the role of LPIN2 mutations in the etiology of Majeed syndrome.
Topics: Amino Acid Sequence; Anemia, Dyserythropoietic, Congenital; Child, Preschool; Diagnosis, Differential; Female; Humans; Molecular Sequence Data; Mutation; Nuclear Proteins; Osteomyelitis; Pedigree; Skin Diseases; Syndrome
PubMed: 17330256
DOI: 10.1002/art.22431