Publications by authors named "Ahmet Gül"

202 Publications

Hemodynamic outcome of different ventilation modes in laparoscopic surgery with exaggerated trendelenburg: a randomised controlled trial.

Braz J Anesthesiol 2021 May 12. Epub 2021 May 12.

Ufuk University Faculty of Medicine, Department of Anesthesiology and Reanimation, Ankara, Turkey.

Purpose: To compare hemodynamic effects of two different modes of ventilation (volume-controlled and pressure-controlled volume guaranteed) in patients undergoing laparoscopic gynecology surgeries with exaggerated Trendelenburg position.

Methods: Thirty patients undergoing laparoscopic gynecology operations were ventilated using either volume-controlled (Group VC) or pressure-controlled volume guaranteed mode (Group PCVG) (n = 15 for both groups). Hemodynamic variables were measured using Pressure Recording Analytical Method by radial artery cannulation in addition to peak and mean airway pressures and expired tidal volume.

Results: The only remarkable finding was a more stable cardiac index in Group PCVG, where other hemodynamic parameters were similar. Expired tidal volume increased in Group VC while peak airway pressure was lower in Group PCVG.

Conclusion: PCV-VG causes less hemodynamic perturbations as measured by Pressure Recording Analytical Method (PRAM) and allows better intraoperative hemodynamic control in exaggerated Trendelenburg position in laparoscopic surgery.
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http://dx.doi.org/10.1016/j.bjane.2021.04.028DOI Listing
May 2021

Inflammatory status might direct ILC and NK cells to IL-17 expressing ILC3 and NK subsets in Behcet's disease.

Immunol Lett 2021 Apr 23;235:1-8. Epub 2021 Apr 23.

Department of Immunology, Aziz Sancar Institute of Experimental Medicine (Aziz Sancar DETAE), Istanbul University, Istanbul, Turkey. Electronic address:

Innate lymphoid cells (ILCs) are lymphoid cells that have important effector and regulatory functions in innate immunity and tissue remodeling. Uncontrolled activation and proliferation of ILCs can contribute to inflammatory autoimmune diseases. Behcet's disease (BD) is a complex systemic inflammatory disorder of unknown etiology. It has been shown that natural killer (NK) cells may play an immunoregulatory role in BD, however the role of ILCs is unknown. In this study, the levels and functions of ILCs and NK cell subsets in BD patients were investigated. Cell surface and cytotoxic granules (perforin and granzyme) expression of NK cells and ILCs were evaluated and labeled according to whole blood lysing protocol in peripheral blood samples obtained from the patients and healthy subjects. Cytokine levels of NK cells were investigated in stimulated peripheral blood mononuclear cells. All data were analyzed by flow cytometry. Total ILC and ILC3 cells were increased in active BD patients compared to inactive BD patients and healthy subjects. There was no significant difference between the patients and healthy subjects regarding NK cell surface and intracellular molecule expression. Although, an increase in IFN-γ and IL-17, and a decrease in IL-4 levels were observed in CD56 NK cell subset of BD patients. Recent studies showed increased neutrophilic infiltration and IL-17 secreting Th17 cells in BD patients. It is known that ILC3cells are similar to Th17 subset regarding their cytokine profile and transcription factor expression patterns. Results of current study may suggest that inflammatory microenvironment in BD patients might direct ILC cells to differentiate into ILC3 subset, and IL-17 released by NK cells might have a role in neutrophilic infiltration.
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http://dx.doi.org/10.1016/j.imlet.2021.04.008DOI Listing
April 2021

A single center survey study of systemic vasculitis and COVID-19 during the first months of pandemic.

Turk J Med Sci 2021 Apr 17. Epub 2021 Apr 17.

Introduction: COVID-19 pandemic created concerns among patients receiving immunosuppressive therapy. Frequency of COVID-19 and impact of lockdown on treatment compliance in patients with vasculitis are largely unknown.

Patients And Method: Patients with ANCA-associated and large vessel vasculitis that have been followed-up in our clinic were contacted by phone and a questionnaire containing home isolation status, treatment adherence and history of COVID-19 between March 1st and June 30th, 2020 was applied.

Results: The survey was applied to 103 patients (F/M: 59/44, mean age: 53.2±12.5). Thirty-three (32%) patients didn?t attend at least one appointment; 98(95.1%) noted that they spent 3 months in home isolation. Five patients (4.8%) received immunosuppressives irregularly and 3(2.9%) developed symptoms due to undertreatment. Four (3.9%) patients admitted to hospital with a suspicion of COVID-19, but none of them had positive PCR or suggestive findings by imaging. COVID-19 diagnosed in a patient with granulomatosis with polyangiitis during hospitalization for disease flare and she died despite treatment.

Discussion: Frequency of COVID-19 was low in patients with vasculitis in our single center cohort during the first months of pandemic. Although outpatient appointments were postponed in one-third of our patients, high compliance with treatment and isolation rules ensured patients with vasculitis overcome this period with minimal morbidity and mortality.
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http://dx.doi.org/10.3906/sag-2010-267DOI Listing
April 2021

Initial complete blood count score and predicting disease progression in COVID-19 patients.

Am J Blood Res 2021 15;11(1):77-83. Epub 2021 Feb 15.

Department of Internal Medicine, İstanbul Medical Faculty, İstanbul University İstanbul, Turkey.

Introduction: Coronavirus has caused a pandemic since it was first detected in Wuhan in December 2019. The mortality rate is high in moderate and severe cases. Our study aimed to screen the CBC parameters as a useful predictive factor for COVID-19 resulting in critical illness.

Methods: A total of 285 patients with positive PCR results were analyzed. The median age was 55 (24-90), and 64.2% of patients were male. Sixty-eight percent of cases were hospitalized with moderate, 32% with severe disease at initial admission.

Results: We found that lymphocyte count <620/mcl, neutrophil-to-lymphocyte ratio (NLR) >6, and platelet to lymphocyte ratio (PLR) >350 were predictive of the outcome. We scored our cohort 0-3 for these three parameters. Patients with a score of 2-3 were more likely to have progressive disease, anti-cytokine treatment, intensive care admission, intubation, and death, compared to patients with a score of 0-1. Additionally, they tended to be hospitalized for longer (median 11.5 days, mean 15.6), compared to those with a score 0 or 1 (median 9 days, mean 11.3). Twenty-eight of 38 cases with scores of 2-3 were discharged (73.6%), whereas the rate was 89% for patients with a score of 0-1 (P=0.009).

Conclusion: Based on the absolute lymphocyte count (<620/mcl, NLR >6, PLR >350), our three-parameter score was able to predict disease progression, and the likelihood of anti-cytokine treatment, intubation, and death. We think that COVID-19 patients presenting with moderate to severe pneumonia, and having scores of 2 or 3 on our scale, should be closely monitored and robustly supported.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010608PMC
February 2021

The effect of tocilizumab, anakinra and prednisolone on antibody response to SARS-CoV-2 in patients with COVID-19: A prospective cohort study with multivariate analysis of factors affecting the antibody response.

Int J Infect Dis 2021 Apr 15;105:756-762. Epub 2021 Mar 15.

Department of Infectious Diseases and Clinical Microbiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Objectives: Disease severity, previous medications and immunosuppressive agents could affect the antibody response against SARS-CoV-2. This study aimed to analyze variables affecting the humoral response to SARS-CoV-2.

Methods: This prospective cohort study included adult patients who recovered from COVID-19 and were admitted to a COVID-19 follow-up unit. Eight patient groups were defined in accordance with the results of thoracic computed tomography (CT), SARS-CoV-2 PCR test, and tocilizumab or anakinra use during active disease. Anti-S IgG antibodies were determined by ELISA in serum samples. Anti-S positive and negative cases were compared.

Results: A total of 518 patients were included in the study. SARS-CoV-2 IgG antibodies were positive in 82.8% of patients. SARS-CoV-2 PCR positivity, extent of lung involvement on CT, and time to antibody testing were independently associated with antibody positivity. Tocilizumab, anakinra or prednisolone use was not a factor affecting the antibody response. The rate of antibody response and sample/CO values among antibody-positive patients showed a linear relationship with the extent of lung involvement on CT.

Conclusions: The use of tocilizumab, anakinra and prednisolone for COVID-19 did not affect the antibody response against SARS-CoV-2. The main driver of antibody response among patients with COVID-19 was the extent of pulmonary involvement on CT.
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http://dx.doi.org/10.1016/j.ijid.2021.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959682PMC
April 2021

A shared motif of hla-dpb1 affecting the susceptibility to pr3-anca positive granulomatosis with polyangiitis: comparative analysis of a Turkish cohort with matched healthy controls.

Rheumatol Int 2021 Feb 5. Epub 2021 Feb 5.

Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Topkapı, Turgut Özal Millet Cd, Fatih, 34093, Istanbul, Turkey.

We aimed to analyse the distribution of HLA Class 2 genotypes which were reported among the genetic risk factors for ANCA-associated vasculitis (AAV) among Turkish patients in comparison with healthy subjects and previously reported data of AAV cohorts. Ninety-eight patients (F/M: 47/51 and mean age: 49 ± 1.14) were enrolled in the study and records of gender and birthplace-matched 196 healthy kidney donors were used as the control group. Patients were classified according to the clinical subgroups and ANCA serotypes (MPO-AAV, PR3-AAV). DNA was isolated from venous blood from all patients, and high-resolution HLA Class 2 genotyping was carried out by using NGS-Omixon Holotype HLA Kit. The frequencies of HLA-DQB1*03:03, - *06:04, and -DPB1*13:01, -*16:01 and -*66:01:00 alleles were significantly higher, and the frequencies of HLA-DQB1*02:02, -DPB1*02:01 and -*04:01 alleles were lower in the PR3-AAV subgroup (n = 53) compared to the controls. Comparison of amino acid sequences of the associated HLA-DPB1 alleles revealed the sequence of D-E-A-V in risk alleles replaced with the G-G-P-M sequence in protective alleles between 84 and 87th positions. Structural analysis of the HLA-DPB1*02:01 showed that this shared position is in the contact area between HLA-DP α and β chains and within pocket 1 of the antigen-binding groove. First HLA genotyping analysis in Turkish AAV patients revealed a negative correlation between PR3-ANCA positivity and certain HLA-DPB1 alleles contradictory to the results reported from European cohorts. Known functional effects of D-E-A-V sequence on HLA-DPB1 support the importance of our finding, but further studies are needed to reveal its pathogenic mechanisms.
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http://dx.doi.org/10.1007/s00296-021-04789-4DOI Listing
February 2021

Defining colchicine resistance/intolerance in patients with familial Mediterranean fever: a modified-Delphi consensus approach.

Rheumatology (Oxford) 2020 Dec 17. Epub 2020 Dec 17.

Division of Paediatric Rheumatology, Department of Paediatrics and Autoinflammation Reference Center Tuebingen, University Hospital Tuebingen, Tuebingen, Germany.

Objectives: Colchicine is the main treatment for familial Mediterranean fever (FMF). Although a number of individuals with FMF are intolerant/resistant to colchicine, there is no standard definition of colchicine resistance/intolerance. We developed a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF that may serve as a guide for clinicians and health authorities.

Methods: A set of statements was identified using a modified-Delphi consensus-based approach. The process involved development of an initial colchicine resistance/intolerance-related questionnaire derived from a systematic literature review. The questionnaire, which was completed by an international panel of 11 adult and pediatric rheumatologists with expertise in FMF, was analysed anonymously. The results informed draft consensus statements that were discussed by a round-table expert panel, using a nominal group technique to agree on the selection and wording of the final statements.

Results: Consensus among the panel was achieved on 8 core statements defining colchicine resistance/intolerance in patients with FMF. A definition of resistance was agreed upon that included recurrent clinical attacks (average one or more attacks per month over a 3-month period), or persistent laboratory inflammation in between attacks. Other core statements recognize the importance of assessing treatment adherence, and the impact of active disease and intolerance to colchicine on quality of life.

Conclusion: Based on expert opinion, a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF were identified to help guide clinicians and health authorities in the management of patients with FMF.
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http://dx.doi.org/10.1093/rheumatology/keaa863DOI Listing
December 2020

The OMERACT Core Set of Domains for Outcome Measures in Behçet Syndrome.

Arthritis Care Res (Hoboken) 2020 Nov 17. Epub 2020 Nov 17.

Division of Rheumatology and Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objective: There is an unmet need for reliable, validated, and widely-accepted outcome measures for randomized clinical trials in Behçet syndrome (BS). The Outcome Measures in Rheumatology Clinical Trials (OMERACT) BS Working Group, a large, multi-disciplinary group of experts in BS and patients with BS, worked to develop a Core Set of data-driven outcome measures for use in all clinical trials of BS.

Methods: The Core Domain Set was developed through a comprehensive, iterative, multi-stage project which included a systematic review, a focus group meeting and qualitative patient interviews, a survey among experts in BS, a Delphi exercise involving both patients and physician-experts in BS, and utilization of the data, insight, and feedback generated by these processes to develop a final Core Domain Set.

Results: All steps were completed and domains were delineated across the organ systems involved in this disease. Since trials in BS often focus on specific manifestations and not the disease in its entirety, the final proposed Core Set includes 5 domains mandatory for study in all trials in BS (disease activity, new organ involvement, quality of life, adverse events, and death) with additional sub-domains mandatory for study of specific organ-systems. The final Core Set was endorsed at the 2018 OMERACT meeting.

Conclusion: The Core Set of Domains in BS provides the foundation through which the international research community, including clinical investigators, patients, biopharmaceutical industry, and government regulatory bodies can harmonize the study of this complex disease, compare findings across studies, and advance development of effective therapies.
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http://dx.doi.org/10.1002/acr.24511DOI Listing
November 2020

Long-term follow-up of 89 patients with giant cell arteritis: a retrospective observational study on disease characteristics, flares and organ damage.

Rheumatol Int 2021 Feb 28;41(2):439-448. Epub 2020 Oct 28.

Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Topkapı, Turgut Ozal Millet Cd, 34093, Fatih / Istanbul, Turkey.

The objective of the study is to investigate the clinical characteristics and long-term prognosis including flares and organ damage in patients with giant cell arteritis (GCA) from a tertiary referral centre and compare these features in different subgroups. In this retrospective observational study, patients with GCA who were followed up in our vasculitis clinic between 1998 and 2018 were evaluated by a predefined protocol. Patients with and without cranial symptoms were compared for clinical and laboratory features, flares and permanent damage findings. Vasculitis Damage Index and Large Vessel Vasculitis Index of Damage were used for damage assessment. Records of 89 patients (median follow-up time 46 months) were analysed; mean time to diagnosis after initial symptom was longer in patients with acute vision loss (11 ± 4 vs. 4.8 ± 1.1 months p = 0.002). EGG (n = 19) was younger (63 ± 2 vs. 69 ± 1 years old p = 0.01); had higher mean CRP (141.8 ± 107.3 vs. 76.6 ± 67.9 mg/dL p = 0.023) and ESR (120.8 ± 25.1 vs. 99.3 ± 24.3 mm/h p = 0.004) at diagnosis. PET-CT detected large vessel vasculitis in 42/48 (87.5%) cases of the entire cohort. Thirty-one patients had flares and proportion of flared patients was significantly higher in patients with cranial symptoms. At least one damage item (DI) was present in 54 (60.7%) patients. The development of damage was found to be associated with flares. Evaluation of our cohort revealed the importance of early diagnosis for prevention of vision loss in GCA. Patients without cranial symptoms were younger, present with higher inflammatory response and for these, PET-CT was the main diagnostic tool. Relapse rate was higher in patients with cranial symptoms. Flares and accompanying corticosteroid treatment may contribute to organ damage in GCA.
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http://dx.doi.org/10.1007/s00296-020-04730-1DOI Listing
February 2021

Intimate partner violence (IPV) types are common among Turkish women from high socioeconomic status and have differing effects on child abuse and contentment with life.

North Clin Istanb 2020 13;7(4):359-365. Epub 2020 Feb 13.

Department of Child and Adolescent Psychiatry, Gulhane Training and Research Hospital, Ankara, Turkey.

Objective: Intimate partner violence (IPV) against women is an important public health problem. In this study, we aimed to investigate the exposure of IPV types, child abuse and decrease in life contentment of married women from high socioeconomic status in Turkey.

Methods: Data were collected using an online/written questionnaire and Contentment with Life Scale. The questionnaire included definitions of physical, emotional, economic and sexual IPV and asked how many times they experienced these types of abuse.

Results: We found that physical, emotional, economic and sexual IPV exposure were 19%, 45.2%, 12.5%, and 6%, respectively, which suggest that IPV types were common in this group, too. Physical child abuse was higher among physical and emotional IPV victims (p=0004, p=0.02, respectively), while emotional child abuse was higher only among physical IPV victims (p=0.01). On the other hand, exposure to economic and sexual IPV was not related to any type of child abuse in this sample (p>0.05). Physical and economic IPV victims were statistically older (p=0.004, p<0.001, respectively), married for longer time (p<0.001 for both) and had relatively lower education level (p<0.001 for both), while sexual IPV victims had lower education level than non-victims (p=0.03). We demonstrated that physical-emotional and sexual intramarital IPV significantly reduce the women's contentment with life scores when compared with non-victims (p=0.02, p<0.001 and p=0.03, respectively).

Conclusion: IPV exposure is also severe among married women with high socioeconomic levels and is associated with child abuse in the family and a decrease in life contentment. Lengthened education period among women with similar socioeconomic levels may be an additional protective factor for IPV by delaying the age of marriage and increasing the individual income.
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http://dx.doi.org/10.14744/nci.2020.46514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521104PMC
February 2020

Letter: is pneumococcal vaccination safe during the COVID-19 pandemic?

Aliment Pharmacol Ther 2020 Sep;52(5):919-920

Division of Rheumathology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

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http://dx.doi.org/10.1111/apt.15903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436511PMC
September 2020

Molecular dynamics simulations provide molecular insights into the role of HLA-B51 in Behçet's disease pathogenesis.

Chem Biol Drug Des 2020 07;96(1):644-658

Department of Chemical and Biological Engineering, College of Engineering, Koc University, Istanbul, Turkey.

Behçet's disease is an inflammatory disorder of unknown etiology. Genetic tendency has an important role in its pathogenesis, and HLA-B51, a class I MHC antigen, has been recognized as the strongest susceptibility factor for Behçet's disease. Despite the confirmation of the association of HLA-B51 with Behçet's disease in different populations, its pathogenic mechanisms remain elusive. HLA-B51 differs in only two amino acids from HLA-B52, other split antigen of HLA-B5, which is not associated with Behçet's disease. These two amino acids are located in the B pocket of the antigen-binding groove, which occupies the second amino acids of the bound peptides. To understand the nature of the HLA-peptide interactions, differences in structure and dynamics of two HLA alleles were investigated by molecular dynamics simulations using YAYDGKDYI, LPRSTVINI, and IPYQDLPHL peptides. For HLA-B51, all bound peptides fluctuated to larger extent than HLA-B52. Free energy profiles of unbinding process for YAYDGKDYI by steered molecular dynamics simulations showed that unbinding from HLA-B52 results in greater free energy differences than HLA-B51. These results suggest the possibility of an instability of HLA-B51 associated with the repertoire of peptides, and this finding may provide significant insight to its pathogenic role in Behçet's disease.
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http://dx.doi.org/10.1111/cbdd.13658DOI Listing
July 2020

Monogenic lupus due to spondyloenchondrodysplasia with spastic paraparesis and intracranial calcification: case-based review.

Rheumatol Int 2020 Nov 20;40(11):1903-1910. Epub 2020 Jul 20.

Department of Pediatric Rheumatology, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.

Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia characterized with platyspondyly and metaphyseal lesions of the long bones mimicking enchondromatosis, resulting in short stature. SPENCD often coexists with neurologic disorders and immune dysregulation. Spasticity, developmental delay and intracranial calcification are main neurologic abnormalities. Large spectrum of immunologic abnormalities may be seen in SPENCD, including immune deficiencies and autoimmune disorders with autoimmune thrombocytopenia and systemic lupus erythematosus as the most common phenotypes. SPENCD is caused by loss of tartrate-resistant acid phosphatase (TRAP) activity, due to homozygous mutations in ACP5, playing a role in non-nucleic acid-related stimulation/regulation of the type I interferon pathway. We present two siblings, 13-year-old girl and 25-year-old boy with SPENCD, from consanguineous parents. Both patients had short stature, platyspondyly, metaphyseal changes, spastic paraparesis, mild intellectual disability, and juvenile-onset SLE. The age at disease-onset was 2 years for girl and 19 years for boy. Both had skin and mucosa involvement. The age at diagnosis of SLE was 4 years for girl, and 19 years for boy. The clinical diagnosis of SPENCD was confirmed by sequencing of ACP5 gene, which revealed a homozygous c.155A > C (p.K52T), a variant reported before as pathogenic. Juvenile-onset SLE accounts for about 15-20% of all SLE cases. But, the onset of SLE before 5-years of age and also monogenic SLE are rare. Our case report and the literature review show the importance of multisystemic evaluation in the diagnosis of SPENCD and to remind the necessity of investigating the monogenic etiology in early-onset and familial SLE cases.
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http://dx.doi.org/10.1007/s00296-020-04653-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369505PMC
November 2020

The efficacy of anti- IL-1 treatment in three patients with coexisting familial Mediterranean fever and multiple sclerosis.

Mult Scler Relat Disord 2020 Oct 24;45:102332. Epub 2020 Jun 24.

Department of Neurology, Cerrahpasa Medical Faculty, University of Istanbul-Cerrahpasa, Istanbul, Turkey.

It has been reported that multiple sclerosis (MS) is more common among patients with familial Mediterranean fever (FMF) than expected in normal population. Also, an association between MEFV gene variants and disease severity in MS has been described. Excessive production of interleukin-1 (IL-1) beta is responsible for FMF pathogenesis, and anti-IL-1 treatment is an effective approach in colchicine-resistant FMF patients. Here, we describe three patients with FMF and coexisting MS who have been treated with anti-IL-1 agents. Our observations suggest that blocking IL-1 is a safe and an effective alternative for colchicine resistant FMF and probably also for associated MS.
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http://dx.doi.org/10.1016/j.msard.2020.102332DOI Listing
October 2020

Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis.

Nat Immunol 2020 08 29;21(8):857-867. Epub 2020 Jun 29.

Inflammatory Disease Section, Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, Bethesda, MD, USA.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1β suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1β specifically in response to Y. pestis. Y. pestis-infected Mefv FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.
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http://dx.doi.org/10.1038/s41590-020-0705-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381377PMC
August 2020

Validation of the adjusted global antiphospholipid syndrome score in a single centre cohort of APS patients from Turkey.

J Thromb Thrombolysis 2021 Feb;51(2):466-474

Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Capa, Fatih, 34093, Istanbul, Turkey.

The adjusted global antiphospholipid syndrome score (aGAPSS) is a recently developed thrombotic risk assessment score that considers the antiphospholipid antibody (aPL) profile and conventional cardiovascular risk factors. In this retrospective study, we aimed to evaluate the validity of the aGAPSS in predicting clinical manifestations (criteria and extra-criteria) of antiphospholipid syndrome (APS) in a single centre cohort of patients. Ninety-eight patients with APS ± systemic lupus erythematosus (SLE) were classified according to clinical manifestations as vascular thrombosis (VT), pregnancy morbidity (PM) or both (VT + PM). The aGAPSS was calculated for each patient as previously defined. Mean aGAPSS of the cohort was calculated as 10.2 ± 3.8. Significantly higher aGAPSS values were seen in VT (n = 58) and VT + PM (n = 29) groups when compared to PM (n = 11) group (10.6 ± 3.7 vs 7.4 ± 2.9, P = 0.005; 10.7 ± 4 vs 7.4 ± 2.9, P = 0.008, respectively), mainly due to lower frequencies of cardiovascular risk factors in PM. Higher aGAPPS values were also associated with recurrent thrombosis (11.6 ± 3.7 vs 9.9 ± 3.6, P = 0.04). Regarding extra-criteria manifestations, patients with livedo reticularis (n = 11) and APS nephropathy (n = 9) had significantly higher aGAPSS values (12.9 ± 3.4 vs 9.9 ± 3.7, P = 0.02; 12.4 ± 2.9 vs 10 ± 3.8, P = 0.04, respectively). The computed AUC demonstrated that aGAPSS values ≥10 had the best diagnostic accuracy for thrombosis. Our results suggest that patients with higher aGAPSS values are at higher risk for developing vascular thrombosis (either first event or recurrence) and extra-criteria manifestations, especially livedo reticularis and APS nephropathy.
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http://dx.doi.org/10.1007/s11239-020-02195-4DOI Listing
February 2021

Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis.

Proc Natl Acad Sci U S A 2020 06 9;117(25):14405-14411. Epub 2020 Jun 9.

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of (rs17753641) is strongly associated with PFAPA (OR 2.13, = 6 × 10). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near , , and were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. alleles may be factors that influence phenotypes along this spectrum as we found new class I and II associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.
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http://dx.doi.org/10.1073/pnas.2002051117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322016PMC
June 2020

Maternal depression, anxiety, psychoticism and paranoid ideation have effects on developmental delay types of infants: A study with clinical infant-mother dyads.

Arch Psychiatr Nurs 2020 06 15;34(3):184-190. Epub 2020 Apr 15.

Department of Child and Adolescent Psychiatry, Gulhane Research and Training Hospital, Ankara, Turkey.

Background: Developmental delay in infancy includes cognitive-language delay, fine motor delay, gross motor delay, and social-self help delay. Delay in one intellectual domain frequently effects the other areas of development; therefore, determining risk factors are essential. In this study, we evaluated the relationship between maternal psychiatric symptoms and developmental delay types of infants who have not a known risk factor and are expected to show healthy development but have some behavioral and developmental problems.

Methods: The sample consisted of 79 infant-mother (26 girls, 53 boys) dyads who had been admitted to the Department of Child and Adolescent Psychiatry at Gulhane Research and Training Hospital over a one year period. Brief Infant-Toddler Social and Emotional Assessment Scale, Brief Symptom Inventory and Ankara Developmental Screening Inventory were used.

Results: The most frequent developmental delay types were fine motor and social -self-help delay in this sample. For all developmentally delayed infants, maternal interpersonal sensitivity, and depression scores were higher than healthy developed ones. Logistic regression analyses revealed the risk factors: Higher maternal paranoid ideation increases the language-cognitive delay; maternal hostility and anxiety increase the gross motor delay; maternal psychoticism increases the social and self-help delay, and maternal depression increases the total development delay of infants.

Conclusion: Maternal depression, anxiety, psychoticism, and paranoid ideation are important risk factors for infants' developmental delay types and should be addressed while evaluating infant-mother dyads in clinical practice.
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http://dx.doi.org/10.1016/j.apnu.2020.04.009DOI Listing
June 2020

COVID-19 is a Real Headache!

Headache 2020 07 27;60(7):1415-1421. Epub 2020 May 27.

Istanbul Faculty of Medicine, Department of Neurology, Headache Center, Istanbul University, Istanbul, Turkey.

After the emergence of a novel coronavirus named SARS-CoV-2, coronavirus disease 2019 (COVID-19) was initially characterized by fever, sore throat, cough, and dyspnea, mainly manifestations of respiratory system. However, other manifestations such as headache, abdominal pain, diarrhea, loss of taste and smell were added to the clinical spectrum, during the course of the COVID-19 pandemic. The reports on the neurological findings are increasing rapidly and headache seems to be the leader on the symptom list. Headache was reported in 11%-34% of the hospitalized COVID-19 patients, but clinical features of these headaches were totally missing in available publications. According to our initial experience, significant features of headache presentation in the symptomatic COVID-19 patients were new-onset, moderate-severe, bilateral headache with pulsating or pressing quality in the temporoparietal, forehead or periorbital region. The most striking features of the headache were sudden to gradual onset and poor response to common analgesics, or high relapse rate, that was limited to the active phase of the COVID-19. Symptomatic COVID-19 patients, around 6%-10%, also reported headache as a presenting symptom. The possible pathophysiological mechanisms of headache include activation of peripheral trigeminal nerve endings by the SARS-CoV-2 directly or through the vasculopathy and/or increased circulating pro-inflammatory cytokines and hypoxia. We concluded that as a common non-respiratory symptom of COVID-19, headache should not be overlooked, and its characteristics should be recorded with scrutiny.
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http://dx.doi.org/10.1111/head.13856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272895PMC
July 2020

An Algorithm for the Diagnosis of Behçet Disease Uveitis in Adults.

Ocul Immunol Inflamm 2020 Apr 14:1-10. Epub 2020 Apr 14.

Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

: To develop an algorithm for the diagnosis of Behçet's disease (BD) uveitis based on ocular findings.: Following an initial survey among uveitis experts, we collected multi-center retrospective data on 211 patients with BD uveitis and 207 patients with other uveitides, and identified ocular findings with a high diagnostic odds ratio (DOR). Subsequently, we collected multi-center prospective data on 127 patients with BD uveitis and 322 controls and developed a diagnostic algorithm using Classification and Regression Tree (CART) analysis and expert opinion.: We identified 10 items with DOR >5. The items that provided the highest accuracy in CART analysis included superficial retinal infiltrate, signs of occlusive retinal vasculitis, and diffuse retinal capillary leakage as well as the absence of granulomatous anterior uveitis or choroiditis in patients with vitritis.: This study provides a diagnostic tree for BD uveitis that needs to be validated in future studies.
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http://dx.doi.org/10.1080/09273948.2020.1736310DOI Listing
April 2020

Voices of adolescent incest victims: A qualitative study on feelings about trauma and expectations of recovery.

Arch Psychiatr Nurs 2020 04 10;34(2):67-74. Epub 2020 Feb 10.

Ankara University School of Medicine, Department of Psychiatry, Ankara, Turkey.

Background: Incest, is a serious social problem facing society and children/adolescents themselves. The purpose of this study is to explore the ways adolescents talk about and give meaning to their experiences of incest concerning cultural, ethnic factors relevant to southeastern of Turkey.

Method: We focused on in-depth interviews of five incest victims (14-16 years girls, from low socioeconomic status in southeastern of Turkey).

Results: Four key themes were constructed from the qualitative analysis: 1. Unable to understand/Delayed meaning-making: Adolescents provided definitive information about the first abuse memory but they were also unable to understand what they had experienced so they delayed meaning making. 2. Dysfunctional coping style with the incest: Adolescents told that they threatened the perpetrators in various phases of incest. 3. Avoidance of eye contact by the perpetrator: We recognized that perpetrators avoided social contact with the victim. This theme evokes dehumanizing of women during incest. 4. The urge to destroy happy memories: This theme presents data on the adolescents' expectations about recovery.

Conclusion: According to the themes, two fundamental therapeutic precepts could guide the treatment process for adolescent girl incest survivors: 1. Exploration of the delayed meaning making: Therapist could address dysfunctional family functioning and explain that it is normal for a child to be delayed in meaning making. 2. Recovery of the adolescent's lost self after semantic dehumanization in abuses: Therapist should help her to dispute irrational beliefs about worthlessness and to gain control of her body.
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http://dx.doi.org/10.1016/j.apnu.2020.02.003DOI Listing
April 2020

Phenotypic variability including Behçet's disease-like manifestations in DADA2 patients due to a homozygous c.973-2A>G splice site mutation.

Clin Exp Rheumatol 2019 Nov-Dec;37 Suppl 121(6):142-146. Epub 2019 Dec 9.

Department of Genetics, University Medical Centre Groningen, The Netherlands.

Objectives: To describe phenotypic and functional characteristics of patients with the homozygous c.973-2A>G splice site mutation in the adenosine deaminase 2 (ADA2) gene (rs139750129), resulting in deficiency of ADA2 (DADA2).

Methods: We present case synopses of six patients from three unrelated families. Clinical data were analysed and next-generation sequencing (NGS) was performed. We also tested for aberrant RNA splicing and measured ADA2 enzyme activity.

Results: One family had common DADA2 symptoms, whereas Behçet's disease-like manifestations were observed in the other two families. We detected the homozygous c.973-2A>G splice site mutation in ADA2 in all patients tested. ADA2 enzyme activity was significantly lower in patients than in healthy controls, but no correlation between ADA2 activity levels and disease severity was observed. Aberrant splicing was detected in a minority of mRNA transcripts, but the formation of other, undetected, aberrant splicing products could not be excluded. Patients were treated with TNF-α inhibitors to prevent recurrence of inflammatory findings including cerebral vasculitis-associated stroke.

Conclusions: We describe three families with the same homozygous splice site mutation in ADA2 and observed a novel combination of manifestations resembling Behçet's disease. This further expands the range of phenotypes caused by ADA2 mutations, although no complete genotype-phenotype association could be determined. Even without active disease, the risk of stroke should be addressed in making decisions regarding treatment of DADA2 patients.
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January 2020

Treatment of Libman-Sacks endocarditis by combination of warfarin and immunosuppressive therapy.

Turk Kardiyol Dern Ars 2019 Dec;47(8):687-690

Department of Cardiology, İstanbul University İstanbul Faculty of Medicine, İstanbul, Turkey.

Antiphospholipid syndrome (APS) is a clinical disorder that creates an increased risk of arterial or venous thrombotic events or pregnancy-associated complications and includes the presence of autoantibodies against negatively charged phospholipids. This syndrome is often associated with systemic autoimmune diseases, such as systemic lupus erythematosus (SLE). Libman-Sacks endocarditis is a form of non-bacterial thrombotic endocarditis and is infrequently seen in APS. There are few data documenting the echocardiographic response of APS valve disease to medical treatment. This is an unusual case of a young female patient with SLE and APS who had chorea and non-bacterial thrombotic aortic valve endocarditis. Echocardiography revealed that the vegetation had receded after a combination of warfarin and immunosuppressive therapy.
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http://dx.doi.org/10.5543/tkda.2019.29213DOI Listing
December 2019

Pseudodominance of autoinflammatory disease in a single Turkish family explained by co-inheritance of haploinsufficiency of A20 and familial Mediterranean fever.

Clin Exp Rheumatol 2019 Nov-Dec;37 Suppl 121(6):89-92. Epub 2019 Jul 15.

Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, MD, USA.

Objectives: We investigated a Turkish family with multiple patients presenting with familial Mediterranean fever (FMF) and Behçet's disease (BD)-like manifestations. The index case and the two daughters with Behçet-like disease, were previously found to have a TNFAIP3 frameshift mutation. The high number of affected cases in this expanded family could be consistent with a dominantly inherited inflammatory disease, although some individuals had clinical features more consistent with recessively inherited FMF. We sequenced DNA from members of this family to determine whether the TNFAIP3 frameshift mutation and/or MEFV variants could explain this autoinflammatory disease pedigree.

Methods: Patients were clinically diagnosed to have FMF or BD. Sanger sequence targeting TNFAIP3 exon 5 and MEFV exon 10 was carried out.

Results: The symptomatic mother of the index case and her affected maternal uncle had compound heterozygous FMF-associated MEFV mutations, p.Met680Ile and p.Arg761His. Two affected daughters of the maternal uncle also had compound heterozygous FMF-associated mutations, p.Met680Ile and p.Val726Ala. The index case and her two affected daughters had a TNFAIP3 frameshift mutation (c.799delG; p.Pro268Leufs*19), which is consistent with their HA20 diagnosis, and also carried a heterozygous MEFV p.Arg761His mutation.

Conclusions: Autoinflammatory disease manifestations in a Turkish family with multiple affected cases could be explained by co-inheritance of pathogenic MEFV variants and a heterozygous HA20-associated mutation. FMF-associated p.Arg761His allele carried with the loss of function TNFAIP3 mutation by all three HA20 patients may contribute to their autoinflammatory phenotype and could also be responsible for their favourable response to colchicine.
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January 2020

Methylphenidate and Central Precocious Puberty: A Probable Side Effect among Seven Children with the Attention Deficit Hyperactivity Disorder.

Clin Psychopharmacol Neurosci 2019 Aug;17(3):446-449

Departments of Psychiatry, Ufuk University School of Medicine, Gulhane Training and Research Hospital, Ankara, Turkey.

Methylphenidate (MPH) is the most preferred drug for treatment of the attention deficit hyperactivity disorder (ADHD). Here, we aimed to discuss the possible effects and mechanisms of MPH on precocious puberty (PP) via a case series with seven children who had normal body mass index. In this case series we evaluated seven children with ADHD, who had received MPH for at least 6 months (0.5 mg/kg/dose three times a day, maximum 60 mg) and admitted to Department of Pediatric Endocrinology with PP symptoms. The mean age was 8.16 years. Basal hormonal levels (luteinizing hormone [LH], follicle stimulating hormone, and estrogen/testosterone) were within normal range. Results of LH-releasing hormone stimulation tests demonstrated central pubertal responses. Glutamine, dopamine and noradrenaline are most important excitatory neurotransmitters that have a role at the beginning of puberty. The effect of MPH, cumulating dopamine and noradrenaline in the synaptic gap could be associated with the acceleration of puberty with the excitatory effect of dopamine’s gonadotropin-releasing hormone (GnRH) release, excitatory effect of noradrenaline’s GnRH release and the disappearance of GnRH receptor expression suppressor effect on prolactin disinhibitory effect.
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http://dx.doi.org/10.9758/cpn.2019.17.3.446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705097PMC
August 2019

Classification criteria for autoinflammatory recurrent fevers.

Ann Rheum Dis 2019 08 24;78(8):1025-1032. Epub 2019 Apr 24.

Division of Medicine, UCL Medical School, Royal Free Campus, National Amyloidosis Centre, London, UK.

Background: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.

Methods: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.

Results: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98).

Conclusion: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
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http://dx.doi.org/10.1136/annrheumdis-2019-215048DOI Listing
August 2019

Clinical course of abdominal aortic aneurysms in Behçet disease: a retrospective analysis.

Rheumatol Int 2019 Jun 19;39(6):1061-1067. Epub 2019 Mar 19.

Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Fatih, 34093, Istanbul, Turkey.

Arterial aneurysms are rare manifestations of Behçet Disease (BD) with high morbidity and mortality. This study aimed to investigate the clinical course of BD patients with abdominal aortic aneurysms (AAA). We retrospectively searched charts of BD patients, followed up between 1988 and 2011, to identify those with AAA with at least 6-month clinical and radiological follow-up data. Chart review revealed 12 patients (11 males) with AAA amongst 1224 patients; follow-up data from 11 patients were available. The most common symptoms were lower back and abdominal pain. The only pre-treatment complication was a spontaneous rupture. All but one patient received corticosteroid and cyclophosphamide pulses for the induction, and corticosteroid and azathioprine for the maintenance treatment; one patient received only the maintenance treatment. Two patients had surgical graft interposition, without postoperative complications. Seven patients had endovascular stenting; five of them (71.4%) showed radiological regression after 32.5 (13.4-53.8) months, while four (57%) had clinical improvement after 11.8 (0.2-29.4) months. However, one non-responsive patient developed stent infection and exsanguinated during percutaneous drainage, and one patient developed femoral artery pseudo-aneurysm at the catheter insertion site. Another patient developed a new aneurysm under the maintenance treatment. Medical treatment alone yielded radiological regression in one of two patients. Current immunosuppressive, surgical or endovascular approaches can provide clinical and radiological improvements lately in BD patients with AAA. Furthermore, complication rates seem to be high with interventional approaches. These findings suggest an unmet need for safer alternative treatments.
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http://dx.doi.org/10.1007/s00296-019-04283-yDOI Listing
June 2019

Update on Outcome Measure Development in Large-vessel Vasculitis: Report from OMERACT 2018.

J Rheumatol 2019 09 15;46(9):1198-1201. Epub 2019 Mar 15.

From the Division of Rheumatology, University of Ottawa, Ottawa Hospital Research Institute; Division of Rheumatology, Department of Medicine, and School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa; Department of Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; University of the West of England; University of Bristol; University Hospitals Bristol National Health Service (NHS) Trust, Bristol; Leeds Institute of Rheumatic and Musculoskeletal Medicine; Leeds Teaching Hospitals NHS Trust, Leeds, UK; Division of Rheumatology and Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Rheumatology, University of California at Los Angeles, Los Angeles, California; Division of Rheumatology and Immunology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Discipline of Medicine, University of Adelaide; The Queen Elizabeth Hospital, Adelaide, Australia; Fatih Sultan Mehmet Training and Research Hospital; Division of Rheumatology, Department of Internal Medicine, Istanbul University, Istanbul Faculty of Medicine; Division of Rheumatology, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul; Division of Rheumatology, Marmara University, School of Medicine, Marmara, Turkey; Department of Internal Medicine, University Paris Diderot, Paris, France; Department of Public Health Sciences, University of Iceland, Reykjavik, Iceland.

Objective: The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group seeks to develop validated outcome measures for use in trials for large-vessel vasculitis (LVV).

Methods: An international Delphi exercise conducted among investigators identified items considered important to measure active disease. In parallel, qualitative research with patients was conducted, including interviews and focus groups.

Results: Next steps prioritized by the group for LVV include (1) defining disease states (remission, flare, and patient-acceptable symptom state) and (2) selection of patient-reported outcome tools.

Conclusion: The ultimate goal is to develop an OMERACT-endorsed core set of outcome measures for use in clinical trials of LVV.
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http://dx.doi.org/10.3899/jrheum.181072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254610PMC
September 2019