Behçet's disease is a complex disease, and genetic susceptibility plays a critical role. This review aimed to discuss the recent genomewide association study (GWAS) findings and their implications to ...the pathogenesis of Behçet's disease.
GWAS data confirmed the major role of HLA-B51 in Behçet's disease susceptibility, and the discovery of epistatic interactions between HLA-B51 and ERAP1 variants provided some hints about its possible pathogenic mechanisms. Investigation of human leukocyte antigen (HLA) Class I region showed weaker but independent associations around HLA-A and HLA-C regions. Genomewide studies also established associations with IL10, IL23R, CCR1, STAT4, KLRC4, GIMAP2/GIMAP4, and UBAC2 genes in Behçet's disease patients of different ethnicities. Deep resequencing of targeted genes identified additional associations with rare variants in TLR4, MEFV, and NOD2 genes.
GWAS data established a major step forward by providing insights into the underlying mechanisms in Behçet's disease with the discovery of new susceptibility genes. These variations may implicate defects in the sensing and processing of microbial and endogenous danger signals as well as in the regulation of innate and adaptive immune responses in Behçet's disease. Association findings with HLA Class I antigens as well as IL23R, ERAP1, IL10, and MEFV genes also suggest shared inflammatory pathways with spondyloarthropathies.
Abstract Familial Mediterranean fever (FMF) is the most common form of monogenic autoinflammatory conditions, and response to colchicine has been considered as one of its distinctive features among ...other hereditary periodic fever disorders. Prophylactic colchicine has been shown to be effective in the prevention of inflammatory attacks and development of amyloidosis. However, the highest tolerable doses of colchicine may not be adequate enough to manage these goals in approximately 5% of FMF patients. Inadequate response to colchicine in fully compliant FMF patients may be associated with genetic and/or environmental factors affecting disease severity and colchicine bioavailability. Clarification of the molecular pathogenic mechanisms of FMF has revealed that interleukin-1 beta (IL-1β) cytokine is the most likely target to attack, and several case reports and case series have already documented the efficacy and safety of available anti-IL-1 agents, such as anakinra, rilonacept, and canakinumab in those patients inadequately responding to colchicine. Characterization and early identification of those FMF patients with uncontrolled inflammatory activity have become more important after the availability of new treatment options for the prevention of disease-associated complications and permanent damages.
Several new treatment modalities with different mechanisms of action have been studied in patients with Behçet's syndrome (BS). The aim of the current effort was to update the recommendations in the ...light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities.
•PSMPU (Problematic Smart Mobile Phone Usage) was detected in 50.6% of the clinical adolescent sample.•Adolescents with problematic smartphone use were older than the others, with lower levels of ...maternal education and self-achievement.•Somatization, interpersonal sensitivity and hostility symptoms predict the risk of problematic smartphone use among adolescents.
Problematic mobile phone use is an important problem which has increasing prevalence among adolescents. We should address risk factors to create intervention frameworks related to this problem. In this study, we aimed to determine the prevalence of problematic smartphone use among adolescents who were referred to clinics, its relationship to sociodemographic characteristics, psychiatric symptoms and emotion regulation problems. We included 150 adolescents aged 12–18 years who own smartphones. All participants filled out the Sociodemographic Information Form, Brief Symptom Inventory (BSI), Difficulties in Emotion Regulation Scale (DERS) and Problematic Mobile Phone Use Scale (PMPUS). Problematic smart phone use was detected in 50.6% of the sample. Adolescents with problematic use were found to be older than the others, with lower levels of maternal education and self-achievement. Regression analysis revealed that the factors predicting the risk of problematic smartphone use are somatization, interpersonal sensitivity and hostility symptoms. According to our results, we suggest psychiatrists consider the high prevalence of problematic smartphone use, address the relationship between hostility, somatic symptoms and interpersonal sensitivity (susceptibility) and the effects of this current problem on social-academic functioning while evaluating and treating adolescents.
This open-label pilot study aimed to investigate the efficacy of canakinumab in colchicine-resistant familial Mediterranean fever (FMF) patients.
Patients with one or more attacks in a month in the ...preceding 3 months despite colchicine were eligible to enter a 30-day run-in period. Patients who had an attack during the first run-in period advanced to a second 30-day period. At the first attack, patients started to receive three canakinumab 150 mg subcutaneous injections at 4-week intervals, and were then followed for an additional 2 months. Primary efficacy outcome measure was the proportion of patients with 50 % or more reduction in attack frequency. Secondary outcome measures included time to next attack following last canakinumab dose and changes in quality of life assessed by SF-36.
Thirteen patients were enrolled in the run-in period and 9 advanced to the treatment period. All 9 patients achieved a 50 % or more reduction in attack frequency, and only one patient had an attack during the treatment period. C-reactive protein and serum amyloid A protein levels remained low throughout the treatment period. Significant improvement was observed in both physical and mental component scores of the Short Form-36 at Day 8. Five patients had an attack during the 2-month follow-up, occurring median 71 (range, 31 to 78) days after the last dose. Adverse events were similar to those observed in the previous canakinumab trials.
Canakinumab was effective at controlling the attack recurrence in patients with FMF resistant to colchicine. Further investigations are warranted to explore canakinumab's potential in the treatment of patients with colchicine resistant FMF.
ClinicalTrials.gov NCT01088880 . Registered 16 March 2010.
Purpose: The purpose of this article is to demonstrate the superiority of gevokizumab as compared to placebo, on top of current standard of care, in reducing the risk of Behçet's disease uveitis ...(BDU) exacerbations.
Methods: Randomized, double-masked, placebo-controlled, parallel group, event-driven trial in BDU patients having recently experienced an ocular exacerbation, subsequently undergoing a tapering procedure from high-dose corticosteroids and receiving 60 mg gevokizumab or placebo every 4 weeks subcutaneously (EYEGUARD B-ClinicalTrials.gov NCT 01965145).
Results: A total of 83 patients (40 gevokizumab, 43 placebo) were included. Gevokizumab did not significantly affect the risk of occurrence of ocular exacerbations. However, data suggested that gevokizumab could preserve visual acuity, reduce the uveitis severity, decrease the emergence of macular edema, and have a corticosteroid sparing effect. Gevokizumab was well tolerated.
Conclusions: While the primary efficacy endpoint was not met with gevokizumab, the control of IL-1β pathway in patients with BDU may still be a relevant target.
Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated with
gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation ...of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (p<0.001). The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%. It performed well for all CAPS subtypes and regardless of
mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.
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