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Familial Mediterranean Fever: Assessing the Overall Clinical Impact and Formulating Treatment Plans.Mediterranean Journal of Hematology and... 2019Recurrent self-limited attacks of fever and short-lived inflammation in the serosal membranes, joints, and skin are the leading features of familial Mediterranean fever... (Review)
Review
Recurrent self-limited attacks of fever and short-lived inflammation in the serosal membranes, joints, and skin are the leading features of familial Mediterranean fever (FMF), the most common autoinflammatory disorder in the world, transmitted as autosomal recessive trait caused by gene mutations. Their consequence is an abnormal function of pyrin, a natural repressor of inflammation, apoptosis, and release of cytokines. FMF-related mutant pyrins are hypophosphorylated following RhoA GTPases' impaired activity and show a propensity to relapsing uncontrolled systemic inflammation with inappropriate response to inflammatory stimuli and leukocyte spread to serosal membranes, joints or skin. Typical FMF phenotype 1 consists of brief episodes of inflammation and serositis, synovitis, and/or erysipelas-like eruption, whereas phenotype 2 is defined by reactive amyloid-associated (AA) amyloidosis, which is the most ominous complication of FMF, in otherwise asymptomatic individuals. Furthermore, FMF phenotype 3 is referred to the presence of two mutations with neither clinical signs of FMF nor AA amyloidosis. The influence of epigenetic and/or environmental factors can contribute to the variable penetrance and phenotypic heterogeneity of FMF. Colchicine, a tricyclic alkaloid with anti-microtubule and anti-inflammatory properties, is the bedrock of FMF management: daily administration of colchicine prevents the recurrence of FMF attacks and the development of secondary AA amyloidosis. Many recent studies have also shown that anti-interleukin-1 treatment is the best therapeutic option for FMF patients nonresponsive or intolerant to colchicine. This review aims to catch readers' attention to the clinical diversity of phenotypes, differential diagnosis, and management of patients with FMF.
PubMed: 31205631
DOI: 10.4084/MJHID.2019.027 -
Cell Reports. Medicine May 2024Systemic lupus erythematosus (SLE) displays a hallmark interferon (IFN) signature. Yet, clinical trials targeting type I IFN (IFN-I) have shown variable efficacy, and...
Systemic lupus erythematosus (SLE) displays a hallmark interferon (IFN) signature. Yet, clinical trials targeting type I IFN (IFN-I) have shown variable efficacy, and blocking IFN-II failed to treat SLE. Here, we show that IFN type levels in SLE vary significantly across clinical and transcriptional endotypes. Whereas skin involvement correlated with IFN-I alone, systemic features like nephritis associated with co-elevation of IFN-I, IFN-II, and IFN-III, indicating additive IFN effects in severe SLE. Notably, while high IFN-II/-III levels without IFN-I had a limited effect on disease activity, IFN-II was linked to IFN-I-independent transcriptional profiles (e.g., OXPHOS and CD8GZMH cells), and IFN-III enhanced IFN-induced gene expression when co-elevated with IFN-I. Moreover, dysregulated IFNs do not explain the IFN signature in 64% of patients or clinical manifestations including cytopenia, serositis, and anti-phospholipid syndrome, implying IFN-independent endotypes in SLE. This study sheds light on mechanisms underlying SLE heterogeneity and the variable response to IFN-targeted therapies in clinical trials.
Topics: Humans; Lupus Erythematosus, Systemic; Interferons; Female; Adult; Male; Transcriptome; Interferon Type I; Middle Aged; Transcription, Genetic; Gene Expression Regulation
PubMed: 38744279
DOI: 10.1016/j.xcrm.2024.101569 -
Nihon Rinsho Men'eki Gakkai Kaishi =... 2011Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent and short duration (1-3 days) of fever, and serositis. Based on... (Review)
Review
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent and short duration (1-3 days) of fever, and serositis. Based on the nationwide survey of FMF in Japan, the estimated number of Japanese FMF patients is about three hundred. High grade fever was observed in 95.5%, chest pain in 35.8% abdominal pain in 62.7% and arthritis in 31.3% among Japanese FMF patients. AA amyloidosis was confirmed in 5 patients (3.7%). Colchicine was effective in 91.8% of Japanese FMF patients. A significant number of FMF patients exist in Japan, and early diagnosis and treatments should be required to prevent AA amyloidosis.
Topics: Adolescent; Adult; Amyloidosis; Child; Child, Preschool; Colchicine; Cytoskeletal Proteins; Early Diagnosis; Familial Mediterranean Fever; Female; Humans; Japan; Male; Middle Aged; Mutation; Pyrin; Treatment Outcome; Young Adult
PubMed: 22041422
DOI: 10.2177/jsci.34.355 -
The Journal of Veterinary Medical... Oct 2023A 31-month-old Holstein dairy cow aborted at 224 days of gestation with ejection of cheese-like lochia. Citrobacter koseri, which commonly exists in the normal flora of...
A 31-month-old Holstein dairy cow aborted at 224 days of gestation with ejection of cheese-like lochia. Citrobacter koseri, which commonly exists in the normal flora of human and animal digestive tracts, was isolated from aborted fetal tissues (liver, spleen, kidney, heart, lung, cerebrum, and skeletal muscle) and fetal membranes. Histopathological examination revealed suppurative fibrinous meningoencephalitis of the cerebrum, cerebellum, and brainstem; suppurative bronchopneumonia; suppurative chorioamnionitis; and fibrous splenic serositis. Numerous gram-negative bacilli were detected in the cytoplasm of macrophages and/or neutrophils in these lesions. Bacteriological investigation and immunohistochemical staining identified the bacilli as C. koseri. This is the first report of cattle abortion caused by C. koseri infection in dairy cattle.
Topics: Female; Animals; Humans; Cattle; Enterobacteriaceae Infections; Citrobacter koseri; Sepsis; Macrophages; Fetus; Cattle Diseases
PubMed: 37661420
DOI: 10.1292/jvms.23-0199 -
Lupus Science & Medicine Dec 2022SLE, primary Sjögren's syndrome (pSS) and systemic sclerosis (SSc) are heterogeneous autoimmune diseases with a dysregulated type I interferon (IFN) system. The...
Autoantibodies associated with systemic sclerosis in three autoimmune diseases imprinted by type I interferon gene dysregulation: a comparison across SLE, primary Sjögren's syndrome and systemic sclerosis.
OBJECTIVE
SLE, primary Sjögren's syndrome (pSS) and systemic sclerosis (SSc) are heterogeneous autoimmune diseases with a dysregulated type I interferon (IFN) system. The diseases often show overlapping clinical manifestations, which may result in diagnostic challenges. We asked to which extent SSc-associated autoantibodies are present in SLE and pSS, and whether these link to serum IFN-α, clinical phenotypes and sex. Samples with clinical data from patients with SSc and healthy blood donors (HBDs) served as controls. Finally, the diagnostic performance of SSc-associated autoantibodies was evaluated.
METHODS
Samples from well-characterised subjects with SLE (n=510), pSS (n=116), SSc (n=57) and HBDs (n=236) were analysed using a commercially available immunoassay (EuroLine Systemic Sclerosis Profile (IgG)). IFN-α was quantified by ELISA. Self-reported data on Raynaud's phenomenon (RP) were available.
RESULTS
With exceptions for anti-Ro52/SSA and anti-Th/To, SSc-associated autoantibodies were more frequent in SSc than in SLE, pSS and HBDs regardless of sex. IFN-α levels correlated with the number of positive SSc-associated autoantibodies (r=0.29, p<0.0001) and associated with Ro52/SSA positivity (p<0.0001). By using data from SLE, SSc and HBDs, RP was significantly associated with topoisomerase I, centromere protein (CENP)-B, RNA polymerase III 11 kDa, RNA polymerase III 155 kDa and PM-Scl100 whereas Ro52/SSA associated inversely with RP. In SLE, CENP-A was associated with immunological disorder, CENP-B with serositis and Ku with lupus nephritis. By combining analysis of ANA (immunofluorescence) with SSc-associated autoantibodies, the diagnostic sensitivity reached 98% and the specificity 33%.
CONCLUSIONS
The 13 specificities included in the EuroLine immunoassay are commonly detected in SSc, but they are also frequent among individuals with other diseases imprinted by type I IFNs. These findings are valuable when interpreting serological data on patients with suspected SSc, especially as patients may present with disease manifestations overlapping different rheumatological diseases. In SLE, we observed associations between manifestations and SSc-associated autoantibodies which have not previously been reported.
Topics: Humans; Autoantibodies; Sjogren's Syndrome; Interferon Type I; RNA Polymerase III; Lupus Erythematosus, Systemic; Scleroderma, Systemic
PubMed: 36581379
DOI: 10.1136/lupus-2022-000732 -
Frontiers in Immunology 2020Familial Mediterranean fever (FMF) is the most common monogenic auto-inflammatory disease characterized by recurrent attacks of fever and serositis. It is associated... (Review)
Review
Familial Mediterranean fever (FMF) is the most common monogenic auto-inflammatory disease characterized by recurrent attacks of fever and serositis. It is associated with mutation in pyrin inflammasome leading to interleukin-1 (IL-1) over secretion. Although colchicine is the first line treatment in FMF, 5-10% of patients are reported in literature as non-responders. Colchicine is not always well-tolerated due either to its direct toxicity or to co-morbidities that preclude the administration of its proper dosage. For these patients an alternative or additional treatment to colchicine is necessary. This literature review reports the published data regarding the use of IL-1 inhibitors in Familial Mediterranean Fever. There is no uniform definition of colchicine resistance, but the different studies of treatment with IL-1 inhibitors provide evidence of IL-1 pathogenic role in colchicine-resistant FMF. IL-1 inhibition is an efficacious option for controlling and preventing flares -at least at the short term- in FMF patients who are insufficiently controlled with colchicine alone. Although canakinumab is the only approved drug in Europe for colchicine resistant FMF treatment, experience with anakinra is also substantial. In the absence of comparative studies both treatments seem to be an equal option for the management of these patients. Overall the safety profile of IL-1 inhibitors seems not different in FMF patients than in the other diseases and can be considered as globally safe. The main side effects are local injection site reactions and infections. IL-1 inhibitors have the potential to improve patient outcome even in FMF patients with co-morbidities or severe complications in whom inflammation control is difficult to achieve with colchicine alone. Nevertheless, current data are limited and further evaluation of long-term efficacy and safety of IL-1 inhibitors are necessary, in order to provide robust evidence in this domain.
Topics: Adolescent; Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Child; Familial Mediterranean Fever; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Male; Middle Aged; Receptors, Interleukin-1; Signal Transduction; Treatment Outcome; Young Adult
PubMed: 32670263
DOI: 10.3389/fimmu.2020.00971 -
Scientific Reports Jun 2023To study the clinical significance of autoantibodies in Chinese patients with new-onset systemic lupus erythematosus (SLE), we enrolled 526 new-onset patients who met...
To study the clinical significance of autoantibodies in Chinese patients with new-onset systemic lupus erythematosus (SLE), we enrolled 526 new-onset patients who met the 1997 Updated American College of Rheumatology SLE Classification Criteria for a retrospective cohort study. Chi-square test and Wilcoxon rank-sum test were used to detect the relationship of autoantibodies with clinical manifestations and serological results respectively. Our results demonstrated that the positive rate of anti-ribosomal P protein (anti-P) antibody in female patients was higher than that in male patients (41.2% vs. 22%, P = 0.008). Patients with anti-SSB (43.95 ± 73.12 vs. 40.92 ± 75.75, P = 0.004; 63.93 ± 103.56 vs. 55.06 ± 120.84, P = 0.008 respectively) antibodies had higher levels of alanine aminotransferase (ALT) and aspartate transaminase (AST), whereas those with anti-P antibody (28.90 ± 25.70 vs. 50.08 ± 93.00, P = 0.014; 38.51 ± 48.19 vs. 69.95 ± 142.67, P = 0.047, respectively) had lower levels of them. Anti-dsDNA antibody (P = 0.021) was associated with pulmonary arterial hypertension (PAH). The patients with anti-Ro60 (P = 0.044), anti-P (P = 0.012) and anti-dsDNA (P = 0.013) antibodies were less likely to develop Interstitial lung disease. Anti-SmRNP antibody was correlated to lower prevalence of neuropsychiatric symptoms (P = 0.037), and patients with anti-centromere antibody (ACA) were more likely to develop serositis (P = 0.016).We identified five clusters of SLE-related autoantibodies, confirmed previously reported associations of autoantibodies, and discovered new associations.
Topics: Humans; Male; Female; Autoantibodies; Retrospective Studies; East Asian People; Lupus Erythematosus, Systemic; Serositis
PubMed: 37344560
DOI: 10.1038/s41598-023-37100-5 -
Frontiers in Microbiology 2023is an emerging swine pathogen with high prevalence worldwide. The main lesions caused are arthritis and polyserositis, and the clinical manifestation of the disease may...
INTRODUCTION
is an emerging swine pathogen with high prevalence worldwide. The main lesions caused are arthritis and polyserositis, and the clinical manifestation of the disease may result in significant economic losses due to decreased weight gain and enhanced medical costs. We aimed to compare two challenge routes to induce infection using the same clinical isolate.
METHODS
Five-week-old, Choice hybrid pigs were inoculated on 2 consecutive days by intravenous route (Group IV-IV) or by intravenous and intraperitoneal routes (Group IV-IP). Mock-infected animals were used as control (control group). After the challenge, the clinical signs were recorded for 28 days, after which the animals were euthanized. Gross pathological and histopathological examinations, PCR detection, isolation, and genotyping of the re-isolated sp. and culture of bacteria other than sp. were carried out. The ELISA test was used to detect anti- immunoglobulins in the sera of all animals.
RESULTS
Pericarditis and polyarthritis were observed in both challenge groups; however, the serositis was more severe in Group IV-IV. Statistically significant differences were detected between the challenged groups and the control group regarding the average daily weight gain, pathological scores, and ELISA titers. Additionally, histopathological scores in Group IV-IV differed significantly from the scores in the control group. All re-isolated strains were the same or a close genetic variant of the original challenge strain.
DISCUSSION
Our results indicate that both challenge routes are suitable for modeling the disease. However, due to the evoked more severe pathological lesions and the application being similar to the hypothesized natural route of infection in Group IV-IV, the two-dose intravenous challenge is recommended by the authors to induce serositis and arthritis associated with infection.
PubMed: 37601388
DOI: 10.3389/fmicb.2023.1209119 -
Current Opinion in Pediatrics Dec 2011Systemic juvenile idiopathic arthritis (SJIA) is an inflammatory condition characterized by fever, lymphadenopathy, rash, arthritis, and serositis. Although the ultimate... (Review)
Review
PURPOSE OF REVIEW
Systemic juvenile idiopathic arthritis (SJIA) is an inflammatory condition characterized by fever, lymphadenopathy, rash, arthritis, and serositis. Although the ultimate cause of this disorder remains elusive, recent work defining cytokine effector mechanisms has led to a new treatment paradigm for this condition. In this review, we describe the recent immunological reclassification of SJIA as an autoinflammatory disorder as well as detailing the dramatic changes in its treatment.
RECENT FINDINGS
SJIA is an autoinflammatory disorder in which defects of innate immune system pathways lead to significant inflammation. Recent studies of the pathophysiology, as well as successful treatment trials, have established interleukin-1β (IL-1β) and IL-6 as key cytokines in the pathogenesis of this condition. As a result, their inhibition has become the centerpiece of the current SJIA treatment paradigm.
SUMMARY
There has been a major shift away from the traditional treatments of SJIA towards therapeutics that inhibit IL-1β and IL-6. In fact, the IL-1 blocker anakinra is now regarded as standard of care for SJIA patients with systemic symptoms, while the IL-6 inhibitor tocilizumab shows great potential. Future research holds promise for the development of more efficient cytokine inhibition as well a more comprehensive knowledge of the innate cytokine networks in this disease.
Topics: Antirheumatic Agents; Arthritis, Juvenile; Autoimmunity; Cytokines; Humans; Treatment Outcome
PubMed: 22045308
DOI: 10.1097/MOP.0b013e32834cba24 -
Seminars in Arthritis and Rheumatism Aug 2017Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory syndrome characterized by recurrent serositis or arthritis attacks and, in some patients, chronic... (Review)
Review
BACKGROUND
Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory syndrome characterized by recurrent serositis or arthritis attacks and, in some patients, chronic subclinical inflammation that predisposes to secondary amyloidosis. Colchicine is the gold standard of treatment, which reduces attack frequency and amyloidosis risk. However, up to 5% of patients are considered resistant or inadequately respond to colchicine, and some others cannot tolerate the side effects of effective doses of colchicine (colchicine intolerant).
METHODS
We examine how the definition of colchicine resistance has evolved along with various characteristics of colchicine that may help explain unresponsiveness to the drug.
RESULTS
Key factors in assessing colchicine resistance include attack frequency and severity, levels of acute phase reactants, colchicine dosage and composition, and treatment compliance. Promising clinical results have been obtained with biologics targeting interleukin-1 in colchicine-resistant or -intolerant patients with FMF.
CONCLUSIONS
These results underscore the need to identify patients who are not optimally managed with colchicine and who might therefore benefit from additional biologic therapies.
Topics: Colchicine; Drug Resistance; Drug Tolerance; Familial Mediterranean Fever; Female; Humans; Male; Medication Adherence; Therapeutics
PubMed: 28413100
DOI: 10.1016/j.semarthrit.2017.03.006