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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 -
Frontiers in Pharmacology 2019P2X7R is an extracellular ATP-gated receptor involved in inflammatory and autoimmune processes mainly acting through NLPR3-inflammasome activation and IL-1β release,...
P2X7R is an extracellular ATP-gated receptor involved in inflammatory and autoimmune processes mainly acting through NLPR3-inflammasome activation and IL-1β release, also implicated in lymphocyte proliferation and cellular apoptosis. Several observations from animal models and patients' studies highlight a possible link between P2X7R-NLRP3 axis and Systemic Lupus Erythematosus (SLE) pathogenesis. The P2X7R-inflammasome axis in addition to the direct production of IL-1β and IL-18, indirectly mediates the release of other cytokines implicated in the pathogenesis of SLE, such as IL-6. The aim of this study was to investigate the role of P2X7R and NLRP3-inflammasome in SLE. Forty-eight SLE patients, 16 with (SLE-S) and 32 without (SLE-NS) history of serositis, and 20 healthy control (HC) subjects were enrolled. Demographic, clinical, and therapeutic data were collected. IL-1β and IL-6 plasma levels were evaluated by ELISA. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood by Ficoll gradient sedimentation and employed as follows: (1) evaluation of P2X7R and NLRP3 expression by RT-PCR; (2) determination of P2X7R activity as Benzoyl ATP (BzATP)-induced [Ca] increments using Fura-2-AM fluorescent probe; (3) isolation of monocytes/macrophages and assessment of IL-1β and IL-6 release following stimulation with lipopolysaccharide (LPS) and BzATP, either separately or in combination. Plasma IL-1β levels were unmodified in SLE respect to HC whereas IL-6 levels were higher in SLE than in HC, resulting significantly increased in SLE-S. Macrophages isolated from SLE patients released lower quantities of IL-1β after stimulation with BzATP, whereas IL-6 release was significantly augmented in SLE-NS respect to both HC and SLE-S after all types of stimulation. The [Ca]i increase following BzATP stimulation was significantly lower in PBMCs from SLE patients than in PBMCs from HC. RT-PCR showed significantly reduced P2X7R and significantly augmented NLRP3 expression in PBMCs from SLE patients. Our data indicate reduced P2X7R expression and function in SLE patients compared with HC and, conversely, increased IL-6 signaling. The possible consequences of reduced P2X7R, mainly on cytokines network deregulation and lymphocyte proliferation, will be further investigated as well as the role of IL-6 as a possible therapeutic target especially in lupus serositis.
PubMed: 31110478
DOI: 10.3389/fphar.2019.00435 -
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 -
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 -
Scientific Reports Jul 2023The aim of this study was to investigate the characteristics of CD4CD40 T cells (Th40 cells) in Chinese systemic lupus erythematosus (SLE) patients. Flow cytometry was...
The aim of this study was to investigate the characteristics of CD4CD40 T cells (Th40 cells) in Chinese systemic lupus erythematosus (SLE) patients. Flow cytometry was used to identify the percentage of Th40 cells in peripheral blood from 24 SLE patients and 24 healthy individuals and the level of IL-2, IL-4, IL-6, IL-10, IFN-r, and TNF-α in serum (22 cases) from the SLE patients. Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2000) was used to assess the SLE disease active state. The percentage of Th40 cells in T cells from SLE patients (19.37 ± 17.43) (%) was significantly higher than that from healthy individuals (4.52 ± 3.16) (%) (P < 0.001). The percentage of Th40 cells was also positively associated with SLEDAI-2000 (P = 0.001) and negatively associated with complement C3 (P = 0.007). The Th40 cell percentage was different in SLE patients with different organs involved. The Th40 cell percentage in SLE patients with lupus serositis (29.29 ± 22.19) was significantly higher than that in patients without serositis (13.41 ± 10.79; P = 0.040), and the percentage in SLE patients with lupus pneumonia involvement (29.11 ± 11.88) was significantly higher than that in patients without lupus pneumonia (16.80 ± 17.99; P = 0.043). After 4 weeks treatment, the Th40 cell percentage decreased significantly (P = 0.005). However, Th40 cell expression was not related to cytokines (IL-2, IL-4, IL-6, IL-10, IFN-r, and TNF-α; P > 0.05). A significantly higher percentage of Th40 cells was found in SLE patients, and the Th40 cell percentage was associated with SLE activity. Thus, Th40 cells may be used as a predictor for SLE disease activity and severity and therapeutic efficacy.
Topics: Humans; Interleukin-10; Interleukin-6; Tumor Necrosis Factor-alpha; Interleukin-2; Interleukin-4; Serositis; Lupus Erythematosus, Systemic; Pneumonia
PubMed: 37400575
DOI: 10.1038/s41598-023-37749-y -
Medicine Jul 2016Systemic lupus erythematosus (SLE) is a chronic autoimmune multiorgan disorder of unknown etiology. It affects both men and women, but with different disease... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Systemic lupus erythematosus (SLE) is a chronic autoimmune multiorgan disorder of unknown etiology. It affects both men and women, but with different disease manifestations of differing disease severity and in varying proportion, with a female predominance of approximately 90%. There have been numerous studies addressing this issue, especially its implications in relation to optimal sex-tailored treatment and improvement of survival rate; however, further research is warranted. A meta-analysis of studies was performed to compare the impact of sex on the clinical outcomes of SLE in different populations.
METHODS
A literature search of the MEDLINE/PubMed and EMBASE databases (until January 2016) was conducted to identify relevant articles. Clinical manifestations reported in these patients were considered as endpoints for this meta-analysis. Two independent reviewers determined eligibility criteria. A fixed-effect model has been used where a small heterogeneity was observed, or else, a random-effect model has been used among the studies. Odd ratio (OR) with 95% confidence interval (CI) was used to express the pooled effect on dichotomous variables, and the pooled analyses were performed with RevMan 5.3.
RESULTS
Sixteen studies consisting of a total of 11,934 SLE patients (10,331 females and 1603 males) have been included in this meta-analysis. The average female-to-male ratio of all the included studies is around 9.3:1. Several statistically significant differences were found: alopecia, photosensitivity, and oral ulcers were significantly higher in female patients (OR 0.36, 95% CI 0.29-0.46, P < 0.00001; OR 0.72, 95% CI 0.63-0.83, P < 0.00001; and OR 0.70, 95% CI 0.60-0.82, P < 0.00001, respectively). Malar rash was significantly higher in female patients (OR 0.68, 95% CI 0.53-0.88, P = 0.003), and arthritis was significantly lower in male patients (OR 0.72, 95% CI 1.25-1.84, P < 0.00001). However, serositis and pleurisies were significantly higher in female patients (OR 1.52, 95% CI 1.25-1.84 P < 0.0001; and OR 1.26, 95% CI 1.07-1.48, P = 0.006, respectively). Renal involvement was higher in male patients (OR 1.51, 95% CI 1.31-1.75, P < 0.00001).
CONCLUSION
The results of this meta-analysis suggest that alopecia, photosensitivity, oral ulcers, arthritis, malar rash, lupus anticoagulant level, and low level of C3 were significantly higher in female lupus patients, whereas renal involvement, serositis and pleurisies, thrombocytopenia, and anti-double stranded deoxyribonucleic acid level were predominant in male patients.
Topics: Female; Humans; Lupus Erythematosus, Systemic; Male; Precision Medicine; Sex Characteristics; Treatment Outcome
PubMed: 27442661
DOI: 10.1097/MD.0000000000004272 -
Lupus Science & Medicine Dec 2021To study whether clinical remission (CR) and Low Lupus Disease Activity State (LLDAS) are achievable goals in childhood-onset SLE.
OBJECTIVES
To study whether clinical remission (CR) and Low Lupus Disease Activity State (LLDAS) are achievable goals in childhood-onset SLE.
METHODS
Data on medication use and disease activity were prospectively collected. LLDAS was defined as Safety of Estrogen in Lupus Erythematosus National Assesment-SLE disease Activity Index (SELENA-SLEDAI) ≤4 with zero scores for renal, Central Nervous System (CNS), serositis, vasculitis and constitutional components, no increase in any SLEDAI component since the previous visit, PGA ≤1, and prednisone dose ≤7.5 mg/day. CR on treatment (Tx) was defined as a Physician Global Assessment <0.5, SELENA-SLEDAI=0, with prednisone ≤5 mg/day and maintenance treatment with immunosuppressives. CR off Tx was the same but without prednisone or other immunosuppressive usage.
RESULTS
51 patients (700 visits) were included. Within 3 months after diagnosis, 94.1% of children were treated with hydroxychloroquine and 60.8% with prednisone. Prednisone dosage decreased from a median of 0.74 mg/kg/day at diagnosis to 0.44 mg/kg/day at 3 months and 0.16 mg/kg/day at 6 months after diagnosis. Use of mycophenolate mofetil increased from 25.5% to 56.9% within 6 months after diagnosis. All children achieved LLDAS (median 186 days) and 72.5% remained in LLDAS >50% of time. 52.9% children achieved CR on Tx, and only 21.6% children achieved CR off Tx.
CONCLUSIONS
LLDAS is an attainable treat-to-target goal in contrast to CR on and off Tx. Even more, LLDAS can be reached with limited use of corticosteroids with early introduction of immunosuppressives.
Topics: Child; Goals; Humans; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Prednisone; Severity of Illness Index
PubMed: 34969874
DOI: 10.1136/lupus-2021-000571 -
BioMed Research International 2021Familial Mediterranean fever (FMF) is the most prevalent autoinflammatory disease. Typical findings are recurrent fever attacks with serositis, skin rash, and synovitis....
Familial Mediterranean fever (FMF) is the most prevalent autoinflammatory disease. Typical findings are recurrent fever attacks with serositis, skin rash, and synovitis. FMF is caused by mutations in the gene, encoding pyrin protein. Pyrin functions in innate immunity and triggers inflammation via inflammatory mediators' production and acts as the primary regulatory component of the inflammasome. On the other hand, various miRNAs play crucial roles in the pathogenesis of different types of cancers and immune-related and neurodegenerative diseases. However, their association with FMF is still unclear. Therefore, in this study, we assessed the roles of selected thirteen miRNAs associated with immune functions. We recruited genetically diagnosed 28 FMF patients and 28 healthy individuals. The expression profiling of the miRNAs was determined by qRT-PCR and normalized to . Our analysis revealed that miR-34a-5p, miR-142-3p, miR-216a-5p, miR-340-5p, miR-429, and miR-582-5p were upregulated, whereas miR-107, miR-569, and miR-1304-5p were downregulated in the FMF patients. Among them, miR-107 was found to be the most remarkable in M694V homozygous mutants compared to other homozygous mutants. During clinical follow-up of the patients with M694V mutation, which is closely related to amyloidosis, evaluation of mir-107 expression might be crucial and suggestive. Our results showed that miRNAs might serve a function in the pathogenesis of FMF. Further studies may provide novel and effective diagnostic and therapeutic agents that target examined miRNAs. Targeting miRNAs in FMF seems to be promising and may yield a new generation of rational therapeutics and diagnostic or monitoring tools enabling FMF treatment.
Topics: Biomarkers; Case-Control Studies; Familial Mediterranean Fever; Homozygote; Humans; MicroRNAs; Mutation; Pyrin
PubMed: 34692839
DOI: 10.1155/2021/6495700 -
ACR Open Rheumatology Dec 2023This study aimed to identify risk factors associated with the development of pulmonary arterial hypertension (PAH) in patients with systemic lupus erythematosus (SLE).
OBJECTIVE
This study aimed to identify risk factors associated with the development of pulmonary arterial hypertension (PAH) in patients with systemic lupus erythematosus (SLE).
METHODS
We conducted a systematic literature review of studies focusing on adult patients classified as having SLE-related PAH by searching the electronic databases Embase, Medline, Medline in-progress, Wanfang, China National Knowledge Infrastructure, Ichushi Web, Kmbase, and KoreaMed. Based on the findings, we conducted a Delphi survey to build expert consensus on issues related to screening for PAH in patients with SLE and on the importance and feasibility of measuring the identified factors in clinical practice.
RESULTS
We included 21 eligible studies for data synthesis. Sixteen factors were associated with an increased risk of SLE-PAH: pericardial effusion, serositis, longer duration of SLE, arthritis, acute and subacute cutaneous lupus, scleroderma pattern on nailfold capillaroscopy, diffusion capacity of carbon monoxide in the lungs (DLCO) <70% predicted, interstitial lung disease, thrombocytopenia, and seven serological factors. Six factors were associated with a decreased risk of SLE-PAH: malar/acute rash, hematologic disorder, renal disorder, higher Systemic Lupus Erythematosus Disease Activity Index score, and two serological factors. Among these, there were six risk factors on which the panelists reached strong or general consensus (peak tricuspid regurgitation velocity on echocardiography >2.8 m/s, pericardial effusion, DLCO <70% predicted, scleroderma pattern on nailfold capillaroscopy, brain natriuretic peptide >50 ng/l, and N-terminal pro-brain natriuretic peptide >300 ng/l). The Delphi panel confirmed the need for a screening tool to identify patients with SLE at high risk of developing PAH and provided consensus on the importance and/or practicality of measuring the identified factors.
CONCLUSION
The risk factors we identified could be used in a screening algorithm to identify patients with SLE with a high risk of developing PAH to facilitate early diagnosis, which could improve prognosis and management of these patients.
PubMed: 37794618
DOI: 10.1002/acr2.11611 -
Minerva Medica Jun 2021
Review
Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Female; Herpesvirus 4, Human; Humans; Infant; Infectious Mononucleosis; Male; Middle Aged; Serositis; Serous Membrane; Young Adult
PubMed: 31638357
DOI: 10.23736/S0026-4806.19.06047-6