Publications by authors named "Seza Ozen"

335 Publications

Spinal involvement in juvenile idiopathic arthritis: what do we miss without imaging?

Rheumatol Int 2021 Jun 11. Epub 2021 Jun 11.

Department of Pediatrics, Division of Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood. Enthesitis-related arthritis (ERA) has been one of the most controversial subtypes of JIA with a higher risk of axial involvement.  Our aim was to assess the frequency and spectrum of MRI findings of spine involvement in patients with JIA and determine if the axial involvement is always clinically symptomatic in patients with positive MRI findings. In this retrospective cross-sectional observational study we included known or suspected JIA patients who underwent spinal MRI examination between 2015 and 2017 and followed up in the Pediatric Rheumatology outpatient clinic. The demographic and clinical data were reviewed from the medical charts and electronic records. All patients were grouped as clinically symptomatic and asymptomatic for spinal involvement and MRI findings were re-evaluated for presence of inflammatory and erosive lesions. Of the 72 JIA patients, 57 (79.2%) were diagnosed with ERA, and 15 (20.8%) with non-ERA subtypes of JIA. Overall, 49 (68%) patients with JIA had positive spinal MRI findings (inflammatory and/or erosive lesions). Twenty-seven (47%) ERA patients were clinically symptomatic for spine involvement and among them, 19 (70.3%) had positive spinal MRI findings. Although 30 ERA (53%) patients were clinically asymptomatic, 23 of them (77%) had positive spinal MRI findings, as well. Eleven (73%) patients diagnosed with non-ERA JIA subtypes were clinically symptomatic for spine involvement at the time of MRI. Among them, four (36.3%) had inflammatory and/or erosive lesions on spine MRI. Four (26%) non-ERA patients were clinically asymptomatic for spine involvement, but three (75%) of them showed positive findings on spinal MRI. Inflammatory and/or erosive lesions of the thoracolumbar spine could exist in patients with JIA, regardless of the presence of symptoms. Not only because the significant proportion of ERA patients show asymptomatic axial involvement but also the presence of axial involvement in patients who were classified as non-ERA depending on current ILAR classification underlines the necessity of using MRI for accurate classification of patients with JIA.
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http://dx.doi.org/10.1007/s00296-021-04890-8DOI Listing
June 2021

Juvenile idiopathic arthritis: lymphocyte activation gene-3 is a central immune receptor in children with oligoarticular subtypes.

Pediatr Res 2021 May 24. Epub 2021 May 24.

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Background: We investigated the role of inhibitory receptors (IRs) and especially lymphocyte activation gene-3 (LAG-3) in the pathogenesis of oligoarticular juvenile idiopathic arthritis (o-JIA).

Methods: Paired samples of synovial fluid (SF) and plasma and peripheral blood (PBMCs) and synovial fluid mononuclear cells (SFMCs) were collected from o-JIA patients along with their clinical data (n = 24). Plasma from healthy controls (n = 14) and paired SF and plasma samples from five non-arthritic juvenile orthopedic patients (n = 5) served as controls. Spontaneously differentiated fibroblast-like synoviocytes (FLSs) from SFMCs were co-cultured with autologous PBMCs/SFMCs and used as ex vivo disease model. Soluble levels and cellular expressions of IRs together with their functional properties in the ex vivo model were analyzed.

Results: In patients with o-JIA, soluble levels of LAG-3 and expression of LAG-3 and T cell immunoglobulin mucin03 (TIM-3) on CD3CD4CD45RO T cells were increased, especially in SF. Major histocompatibility complex (MHC) class II expression was induced on FLSs when these were co-cultured with autologous PBMCs/SFMCs, together with an increased monocyte chemoattractant protein-1 (MCP-1) production. In PBMC and FLS + PBMC co-cultures, neutralizing antibodies to IRs were added. Only anti-LAG-3 antibodies significantly increased MCP-1 secretion. The addition of agonistic LAG-3 antibody resulted in decreased effector cytokine secretion.

Conclusions: This is the first report comparing the effects of different IRs in o-JIA and suggests that LAG-3 might contribute to the pathogenesis of this disease.

Impact: This is the first study addressing the role of different co-IRs in o-JIA. We showed that LAG-3 and TIM-3 seem more important in juvenile arthritis in contrast to adult rheumatoid arthritis, where cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death-1 were reported to be more important. We designed an ex vivo disease model for o-JIA, examined the effects of co-IRs in this model, and demonstrated that they might contribute to the pathogenesis of the disease. LAG-3 might play a role in o-JIA pathogenesis and might be a potential therapeutic option for o-JIA patients.
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http://dx.doi.org/10.1038/s41390-021-01588-2DOI Listing
May 2021

Favipiravir use in children with COVID-19 and acute kidney injury: is it safe?

Pediatr Nephrol 2021 May 22. Epub 2021 May 22.

Department of Pediatric Infectious Diseases, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Background: The rising number of infections due to Severe Acute Respiratory Syndrome Coronavirus-2 (popularly known as COVID-19) has brought to the fore new antiviral drugs as possible treatments, including favipiravir. However, there is currently no data regarding the safety of this drug in patients with kidney impairment. The aim of this paper, therefore, is to share our experience of the use of favipiravir in pediatric patients affected by COVID-19 with any degree of kidney impairment.

Methods: The study enrolled pediatric patients aged under 18 years and confirmed as suffering from COVID-19 and multisystem inflammatory syndrome in children (MIS-C) with any degree of kidney injury, who were treated with favipiravir at the time of admission.

Results: Out of a total of 11 patients, 7 were diagnosed with MIS-C and 4 with severe COVID-19. The median age of the cases was 15.45 (9-17.8) years and the male/female ratio was 7/4. At the time of admission, the median serum creatinine level was 1.1 mg/dl. Nine patients were treated with favipiravir for 5 days, and 2 patients for 5 days followed by remdesivir for 5-10 days despite kidney injury at the time of admission. Seven patients underwent plasma exchange for MIS-C while 2 severely affected cases underwent continuous kidney replacement therapy (CKRT) as well. One severe COVID-19 patient received plasma exchange as well as CKRT. Serum creatinine values returned to normal in mean 3.07 days.

Conclusions: Favipiravir seems a suitable therapeutic option in patients affected by COVID-19 with kidney injury without a need for dose adjustment.
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http://dx.doi.org/10.1007/s00467-021-05111-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140325PMC
May 2021

Identification of a shared genetic risk locus for Kawasaki disease and IgA vasculitis by a cross-phenotype meta-analysis.

Rheumatology (Oxford) 2021 May 16. Epub 2021 May 16.

Unidad de Enfermedades Autoinmunes Sistémicas, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain.

Objectives: Combination of genomic data of different pathologies as a single phenotype has emerged as a useful strategy to identify genetic risk loci shared among immune-mediated diseases. Our study aimed to increase our knowledge of the genetic contribution to Kawasaki disease (kDa) and IgA vasculitis (IgAV) by performing the first comprehensive large-scale analysis on the genetic overlap between both pediatric vasculitis.

Methods: A total of 1,190 vasculitis patients and 11 302 healthy controls were analyzed. First, in the discovery phase, genome-wide data of 405 kDa patients and 6,252 controls and 215 IgAV patients and 1,324 controls, all of European origin, were combined using an inverse variance meta-analysis. Second, the top associated polymorphisms were selected for replication in additional independent cohorts (570 cases and 3,726 controls). Polymorphisms with p-values ≤ 5x1 0 -8 in the global IgAV-kDa meta-analysis were considered as shared genetic risk loci.

Results: A genetic variant, rs3743841, located in an intron of the NAGPA gene, reached genome-wide significance in the cross-disease meta-analysis (p= 8.06x10-10). Additionally, when IgAV was individually analyzed, a strong association between rs3743841 and this vasculitis was also evident (p= 1.25x10-7; OR (95% CI)=1.47 (1.27-1.69)). In silico functional annotation showed that this polymorphism acts as a regulatory variant modulating the expression levels of the NAGPA and SEC14L5 genes.

Conclusion: We have identified a new risk locus with pleiotropic effects on the two vasculitis of childhood analyzed. This locus represents the strongest non-HLA signal described for IgAV to date.
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http://dx.doi.org/10.1093/rheumatology/keab443DOI Listing
May 2021

IgG4-related disease in pediatric patients: a single-center experience.

Rheumatol Int 2021 May 12. Epub 2021 May 12.

Department of Pediatric Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Objective: Immunoglobulin G4-related disease (IgG4-RD) is a systemic, immune-mediated, and fibroinflammatory disease that can affect almost any organ system. We aimed to present our single-center experience of pediatric patients with IgG4-RD, a rare disease in children.

Methods: Pediatric patients diagnosed with IgG4-RD at the Hacettepe University between June 2014 and September 2020 were evaluated retrospectively. Patients with definite, probable, or possible diagnosis of IgG4-RD were included.

Results: A total of eight patients with a median age of 13.4 (IQR 9.5-15.0) years were included in the study. Clinical presentations were IgG4-related ophthalmic disease in six patients, IgG4-related lymphadenopathy in one patient, and IgG4-related sialadenitis and lymphadenopathy of several lymph nodes accompanied by pancreatitis, ulcerative colitis, and pulmonary manifestations in one patient. Elevated serum IgG4 was detected in three of eight patients (37.5%). The main histopathological feature was fibrosis and lymphoplasmacytic infiltrates. Corticosteroids were used as first-line treatment in almost all patients with or without steroid-sparing agents. Azathioprine, methotrexate and rituximab were used as steroid-sparing agents. Relapse occurred in two of seven patients. Radiotherapy was used as the last resort in one patient with severe orbital disease.

Conclusion: IgG4 RD mainly presents with orbital manifestations in pediatric population but has wide phenotypic clinical variability. Although rare, early recognition and treatment are essential for a better outcome in these patients.
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http://dx.doi.org/10.1007/s00296-021-04885-5DOI Listing
May 2021

The pyrin inflammasome aggravates inflammatory cell migration in patients with familial Mediterranean fever.

Pediatr Res 2021 May 7. Epub 2021 May 7.

Department of Medical Biology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Background: Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by pathogenic variants of the MEFV gene, which encodes pyrin. Leukocyte migration to serosal sites is a key event during inflammation in FMF. The pyrin inflammasome is a multiprotein complex involved in inflammation. Here, we aimed to determine the relationship between inflammatory cell migration and the pyrin inflammasome in FMF patients.

Methods: Monocytes were isolated from blood samples collected from patients with FMF, healthy controls, and a patient with cryopyrin-associated periodic syndrome (CAPS), which served as a disease control. Inflammasome proteins were analyzed under inflammasome activation and inhibition by western blotting. Cell migration assays were performed with the isolated primary monocytes as well as THP-1 monocytes and THP-1-derived macrophages.

Results: When the pyrin inflammasome was suppressed, migration of monocytes from FMF patients was significantly decreased compared to the migration of monocytes from the CAPS patient and healthy controls. Cell line experiments showed a relationship between pyrin inflammasome activation and cell migration.

Conclusions: These findings suggest that the increased cell migration in FMF is due to the presence of more active pyrin inflammasome. This study contributes to our understanding of the role of pyrin in inflammatory cell migration through inflammasome formation.

Impact: The pyrin inflammasome may play a role in inflammatory cell migration. FMF patients show a pyrin inflammasome-dependent increase in inflammatory cell migration. Correlations between the pyrin inflammasome and cell migration were observed in both THP-1 monocytes and THP-1-derived macrophages.
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http://dx.doi.org/10.1038/s41390-021-01559-7DOI Listing
May 2021

Systematic review of childhood-onset polyarteritis nodosa and DADA2.

Semin Arthritis Rheum 2021 Jun 19;51(3):559-564. Epub 2021 Apr 19.

Division of Rheumatology, Department of Pediatrics, Hacettepe University Faculty of Medicine, and Hacettepe University Vasculitis Research Center, Ankara, 06100, Turkey. Electronic address:

Background: Diagnosis of childhood polyarteritis nodosa (PAN) has become challenging after the definition of deficiency of adenosine deaminase 2 (DADA2). We aimed to define the differential features of pediatric PAN and DADA2 patients in our center and in the literature.

Methods: The charts of pediatric PAN and DADA2 patients followed at the Pediatric Rheumatology Unit of Hacettepe University between 2010-2020 were analyzed. A systematic literature review was conducted for articles regarding pediatric PAN or DADA2.

Results: Thirty-four pediatric PAN and 18 pediatric DADA2 patients were included. The age at onset was younger, parental consanguinity, livedo reticularis, neurologic involvement (especially strokes), lymphopenia, and hypogammaglobulinemia were more frequent, while thrombocytosis and panniculitis were less frequent in DADA2 patients. The primary treatment was anti-tumor necrosis factor (anti-TNF) in DADA2. For induction treatment, all systemic PAN patients received corticosteroids, and cyclophosphamide (n=11) or mycophenolate mofetil (MMF) (n = 3). Cyclophosphamide was replaced with MMF in nine once remission was confirmed with PVAS. In the literature, 28 articles describing 613 pediatric PAN patients and 26 articles describing 207 pediatric DADA2 patients were identified. Neurologic, gastrointestinal, and cardiac involvements were more frequent in DADA2, while constitutional symptoms and testis involvement were more common in PAN.

Conclusion: In a child with PAN-like phenotype, DADA2 should be considered in the presence of young age at disease onset, parental consanguinity, strokes, lymphopenia, and lack of thrombocytosis during active disease. Anti-TNF treatment is indicated for vasculitic DADA2. Cyclophosphamide could be switched to MMF when remission is confirmed with PVAS in severe PAN.
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http://dx.doi.org/10.1016/j.semarthrit.2021.04.009DOI Listing
June 2021

LONG TERM RENAL SURVIVAL OF PEDIATRIC PATIENTS WITH LUPUS NEPHRITIS.

Nephrol Dial Transplant 2021 Apr 7. Epub 2021 Apr 7.

Department of Pediatrics, Division of Nephrology, Hacettepe University Faculty of Medicine Ankara, Turkey.

Background: Childhood-onset systemic lupus erythematosus (SLE) is more severe than adult-onset disease, including more frequent kidney involvement. This study aimed to investigate baseline clinical features, treatment modalities, short- and long-term renal outcomes of pediatric patients with lupus nephritis (LN).

Materials And Methods: This study enrolled 53 LN patients out of 102 childhood-onset SLE patients followed at Hacettepe University between 2000-2020. The demographic and clinical data were reviewed retrospectively from the medical charts and electronic records. All SLE patients with renal involvement underwent renal biopsy either at the time of diagnosis or during follow-up.

Results: The median age at onset of SLE was 13.3 (IQR : 10.4-15.8) years. The median follow-up duration was 43.1 (IQR : 24.3-69.3) months. Of the 102 SLE patients, 53 patients (52%) had lupus nephritis (LN). The most frequent histopathological class was class IV LN (54.7%), followed by class III LN (22.6%). The proportion of patients who achieved either complete or partial remission were 77.3% and 73% at 6 and 12 months, respectively. In the overall LN cohort, 5- and 10-year renal survival rates were 92% and 85.7%, respectively. The remission rate at 6th month was significantly higher in Mycophenolate mofetil (MMF) and Cyclophosphamide (CYC) treated groups than other combination therapies (p = 0.02). Although no difference was found between the CYC and MMF response rates (p = 0.57), in the proliferative LN (Class III and IV), the vast majority of class IV patients (%79) received CYC as induction threapy. There was no difference between the response rates in any treatment regimens at 12th month (p = 0.56). In the multivariate analysis; male gender, requiring dialysis at the time of LN diagnosis, failure to achieve remission at 6th and at 12 th months were found to be associated with poor renal outcome.

Conclusion: Our study demonstrated that male gender, failure to achieve remission at 6th and at 12 th months, and requiring dialysis at the time of diagnosis were the best predictors of poor renal outcome. Therefore, appropriate and agressive management of pediatric LN is essential to achieve and maintain remisson.
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http://dx.doi.org/10.1093/ndt/gfab152DOI Listing
April 2021

Mycophenolate mofetil versus cyclophosphamide for remission induction in childhood polyarteritis nodosa: An open label, randomised, Bayesian, non-inferiority trial.

Arthritis Rheumatol 2021 Mar 24. Epub 2021 Mar 24.

Inflammation Immunology and Rheumatology Section, University College London Great Ormond Institute of Child Health, Department of Paediatric Rheumatology, Great Ormond Street Hospital NHS Foundation Trust, London, UK.

Objective: Cyclophosphamide (CYC) is used in clinical practice off-label for induction of remission of childhood polyarteritis nodosa (cPAN). Mycophenolate mofetil (MMF) might offer a less toxic alternative: we explored their relative effectiveness in a randomised controlled trial (RCT).

Methods: International, open-label, Bayesian, RCT investigating the relative effectiveness of MMF and CYC for remission induction in cPAN. Eleven newly-diagnosed patients were randomised (1:1) to MMF or intravenous-CYC; all received the same glucocorticoid regimen. The primary endpoint was remission within 6-months whilst compliant with glucocorticoid taper. Bayesian distributions for remission rates were established a priori for MMF and CYC by experienced clinicians, and updated to posterior distributions on trial completion.

Results: Baseline disease activity/features were similar between groups. The primary remission endpoint occurred in 4/6 patients (67%) in the MMF group and 4/5 patients (80%) in the CYC group. Time to remission was shorter in the MMF group (median 7.4 weeks versus 17.5 weeks for CYC). No relapses occurred in either group within 18-months. Two serious infections were probably related to MMF. Physical and psychosocial quality-of-life scores were superior in the MMF group compared to CYC at 6-and 18-months. Combining the prior expert opinion with results from MYPAN provided posterior estimates of remission of 71% (90% CrI 51-83%) for MMF; and 75% (90% CrI 57-86%) for CYC.

Conclusion: Taking the prior opinion and the study results together, rates of remission induction in cPAN on MMF and CYC are similar, and MMF might be associated with better health-related quality of life than CYC.
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http://dx.doi.org/10.1002/art.41730DOI Listing
March 2021

Comparison of IVIG resistance predictive models in Kawasaki disease.

Pediatr Res 2021 Mar 22. Epub 2021 Mar 22.

Division of Pediatric Rheumatology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Background: We aimed to compare the ten different scores (by Kobayashi, Egami, Harada, Formosa, Sano, Piram et al., Wu et al., Yang et al., Tan et al., and Kanai et al.) to assess their performance in predicting IVIG resistance in Turkish children.

Methods: Complete and incomplete KD patients diagnosed with KD at Hacettepe University between June 2007 and September 2019 were evaluated retrospectively.

Results: A total of 129 patients, 79 boys (61.2%), with a median age 36 (IQR 19.5-57.0) months were evaluated. Sixteen patients (12.4%) had IVIG resistance. Sensitivity was low for all the ten scores. Tan, Sano, and Egami predictive models had the highest specificity (97.3, 89.4, 86.7%, respectively). Almost all scoring systems distinguished the group of patients with low risk for IVIG resistance but could not differentiate IVIG-resistant patients. Multivariate analysis for the laboratory features showed that platelet count <300 × 10/L and GGT serum levels were independent risk factors for IVIG resistance (OR: 3.896; 95% CI: 1.054-14.404; p = 0.042 and OR: 1.008; 95% CI: 1.001-1.015; p = 0.050).

Conclusions: The current scoring systems had a low sensitivity for predicting the risk for IVIG resistance in Turkish children. On the other hand, increased serum GGT levels and low platelet count were risk factors for predicting IVIG resistance.

Impact: Intravenous immunoglobulin (IVIG) resistance may be observed in 10-20% of patients diagnosed with Kawasaki disease. Coronary artery involvement is more frequent in IVIG-resistant patients. It is important to predict the patients who might develop IVIG resistance to improve prognosis. The performance of the IVIG resistance predictive models in Kawasaki disease in our population is limited due to the low sensitivity.
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http://dx.doi.org/10.1038/s41390-021-01459-wDOI Listing
March 2021

Biological classification of childhood arthritis: roadmap to a molecular nomenclature.

Nat Rev Rheumatol 2021 May 17;17(5):257-269. Epub 2021 Mar 17.

IRCCS Istituto Giannina Gaslini, Genova, Italy.

Chronic inflammatory arthritis in childhood is heterogeneous in presentation and course. Most forms exhibit clinical and genetic similarity to arthritis of adult onset, although at least one phenotype might be restricted to children. Nevertheless, paediatric and adult rheumatologists have historically addressed disease classification separately, yielding a juvenile idiopathic arthritis (JIA) nomenclature that exhibits no terminological overlap with adult-onset arthritis. Accumulating clinical, genetic and mechanistic data reveal the critical limitations of this strategy, necessitating a new approach to defining biological categories within JIA. In this Review, we provide an overview of the current evidence for biological subgroups of arthritis in children, delineate forms that seem contiguous with adult-onset arthritis, and consider integrative genetic and bioinformatic strategies to identify discrete entities within inflammatory arthritis across all ages.
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http://dx.doi.org/10.1038/s41584-021-00590-6DOI Listing
May 2021

Galectin-3: a new biomarker for differentiating periodic fever, adenitis, pharyngitis, aphthous stomatitis (PFAPA) syndrome from familial Mediterranean fever?

Rheumatol Int 2021 Mar 11. Epub 2021 Mar 11.

Division of Rheumatology, Department of Pediatrics, Hacettepe University Faculty of Medicine, 06100, Ankara, Turkey.

Differentiating PFAPA (periodic fever, aphthosis, pharyngitis, and adenitis) syndrome from familial Mediterranean fever (FMF) could be challenging in some cases. Galectin-3 is a lectin with regulatory functions in apoptosis and inflammation. We aimed to test whether galectin-3 could be a biomarker for differentiating PFAPA syndrome from FMF. Patients with PFAPA syndrome, FMF, cryopyrin-associated periodic syndrome (CAPS), and streptococcal pharyngitis, and healthy controls were included in this study. Serum galectin-3 levels were measured using enzyme-linked immunosorbent assay. Eighty-seven patients (36 with PFAPA, 39 with FMF, 8 with CAPS, 4 with streptococcal pharyngitis), and 17 healthy controls were included. Blood samples were drawn during attacks from 20 PFAPA and 7 FMF patients and attack-free periods from 22 PFAPA, 35 FMF, and 8 CAPS patients. The median serum galectin-3 level in the PFAPA-attack group (1.025 ng/ml) was significantly lower than the levels in healthy control (2.367 ng/ml), streptococcal pharyngitis (3.021 ng/ml), FMF attack (2.402 ng/ml), and FMF-attack-free groups (2.797 ng/ml) (p = 0.006, 0.03, 0.01, and < 0.001, respectively). PFAPA-attack-free group had lower galectin-3 levels than the FMF-attack-free group (1.794 vs. 2.797 ng/ml, respectively; p = 0.01). Galectin-3 levels did not differ significantly between CAPS and attack-free PFAPA patients (1.439 ng/ml vs. 1.794 ng/ml, respectively; p = 0.63). In our study, for the first time, we defined galectin-3 as a promising biomarker that differs between PFAPA and FMF patients during both disease flares and attack-free periods. Further studies with high number of patients could validate its role as a biomarker.
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http://dx.doi.org/10.1007/s00296-021-04827-1DOI Listing
March 2021

Plasma checkpoint protein levels and galectin-9 in juvenile systemic lupus erythematosus.

Lupus 2021 May 10;30(6):998-1004. Epub 2021 Mar 10.

Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University, Ankara, Turkey.

SLE is a disease of the adaptive immune system where T lymphocyte dysfunction has an important role as well. We assessed the plasma levels of checkpoint receptors expressed on T cells, along with Galectin-9 to reflect type-1 IFN activity and IL-2Rα in childhood SLE patients. Forty-nine children with SLE and15 healthy controls were included. SLEDAI scores were evaluated at the time of sampling. CD25 (IL-2Rα), 4-1BB, B7.2 (CD86), TGF-β1, CTLA-4, PD-L1, PD-1, Tim-3, LAG- 3, Galectin-9 levels were studied by cytometric bead-based multiplex assay panel. Galectin-9 and PD-L1 were significantly higher in SLE patients. Other checkpoint proteins and IL-2Rα were also higher but did not reach statistical significance. There were significant correlations between SLEDAI and IL-2Rα, Galectin-9 and PDL1. There were three clinical clusters: Cluster 1 included patients with no major organ involvement, cluster 2 had predominantly haematological involvement(n=16) and cluster 3 (n=11) had predominantly renal involvement. Checkpoint proteins were not different among these three clusters. Our data supports that Galectin 9 and IL-2Rα are good markers for disease activity in childhood SLE. We need larger series to evaluate differences between disease clusters in SLE. We failed to show a significant correlation with checkpoint proteins and SLEDAI except for PDL1.
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http://dx.doi.org/10.1177/09612033211002275DOI Listing
May 2021

Genetic disorders with symptoms mimicking rheumatologic diseases: A single-center retrospective study.

Eur J Med Genet 2021 Apr 2;64(4):104185. Epub 2021 Mar 2.

Department of Pediatric Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey. Electronic address:

Musculoskeletal symptoms may be due to noninflammatory causes, including genetic disorders. We aimed to examine the final genetic diagnosis in patients who presented with musculoskeletal complaints to the rheumatology department. Patients who presented to the Department of Pediatric Rheumatology and were referred to the pediatric genetic department between January 2015 and May 2019 were evaluated retrospectively. A total of 60 patients, 19 boys (31.66%), with a mean age of 12.46 ± 1.41 years were included in the study. The total consanguinity rate was 25%. The most common (29.5%) cause of referral to the pediatric genetic department was the presence of skeletal anomalies (such as camptodactyly, clinodactyly, and short stature) with accompanying joint findings. Approximately one-third of the patients (n: 19) were diagnosed and followed up by the pediatric genetics department. The diagnoses of patients were as follows: camptodactyly, arthropathy, coxa vara, and pericarditis (CACP) syndrome (n: 3); trichorhinophalangeal syndrome (n: 1); progressive pseudorheumatoid dysplasia (n: 2); LIG4 syndrome (n: 1); H syndrome (n: 1); spondyloenchondrodysplasia (SPENCD) (n: 3); and nonspecific connective tissue disorders (n: 8). In the differential diagnosis of patients who are referred to the Department of Pediatric Rheumatology with complaints of the musculoskeletal system, genetic disorders should also be considered.
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http://dx.doi.org/10.1016/j.ejmg.2021.104185DOI Listing
April 2021

Hemophagocytosis in bone marrow aspirates in multisystem inflammatory syndrome in children.

Pediatr Blood Cancer 2021 Jun 22;68(6):e28931. Epub 2021 Feb 22.

Department of Pediatric Infectious Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey.

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http://dx.doi.org/10.1002/pbc.28931DOI Listing
June 2021

Multisystem inflammatory syndrome in children during the COVID-19 pandemic in Turkey: first report from the Eastern Mediterranean.

Clin Rheumatol 2021 Feb 12. Epub 2021 Feb 12.

Faculty of Medicine, Department of Pediatrics, Division of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.

Objective: We aimed to describe the typical clinical and laboratory features and treatment of children diagnosed with multisystem inflammatory syndrome in children (MIS-C) and to understand the differences as compared to severe/critical pediatric cases with COVID-19 in an eastern Mediterranean country.

Methods: Children (aged <18 years) who diagnosed with MIS-C and severe/critical pediatric cases with COVID-19 and were admitted to hospital between March 26 and November 3, 2020 were enrolled in the study.

Results: A total of 52 patients, 22 patients diagnosed with COVID-19 with severe/critical disease course and 30 patients diagnosed with MIS-C, were included in the study. Although severe COVID-19 cases and cases with MIS-C share many clinical and laboratory features, MIS-C cases had longer fever duration and higher rate of the existence of rash, conjunctival injection, peripheral edema, abdominal pain, altered mental status, and myalgia than in severe cases (p<0.001 for each). Of all, 53.3% of MIS-C cases had the evidence of myocardial involvement as compared to severe cases (27.2%). Additionally, C-reactive protein (CRP) and white blood cell (WBC) are the independent predictors for the diagnosis of MIS-C, particularly in the existence of conjunctival injection and rash. Corticosteroids, intravenous immunoglobulin (IVIG), and biologic immunomodulatory treatments were mainly used in MIS-C cases rather than cases with severe disease course. There were only three deaths among 52 patients, one of whom had Burkitt lymphoma and the two cases with severe COVID-19 of late referral.

Conclusion: Differences between clinical presentations, acute phase responses, organ involvements, and management strategies indicate that MIS-C might be a distinct immunopathogenic disease as compared to pediatric COVID-19. Conjunctival injection and higher CRP and low WBC count are reliable diagnostic parameters for MIS-C cases. Key Points • MIS-C cases had longer fever duration and higher rate of the existence of rash, conjunctival injection, peripheral edema, abdominal pain, altered mental status, and myalgia than in severe/critical pediatric cases with COVID-19. • Higher CRP and low total WBC count are the independent predictors for the diagnosis of MIS-C. • MIS-C might be a distinct immunopathogenic disease as compared to pediatric COVID-19.
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http://dx.doi.org/10.1007/s10067-021-05631-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879406PMC
February 2021

Penile involvement of immunoglobulin a vasculitis/Henoch-Schönlein purpura.

J Pediatr Urol 2021 Jan 22. Epub 2021 Jan 22.

Department of Pediatrics, Division of Rheumatology, Hacettepe University School of Medicine, Ankara, Turkey. Electronic address:

Background: Immunoglobulin A vasculitis/Henoch-Schönlein purpura (IgAV/HSP) is a leukocytoclasia vasculitis of childhood, predominantly affecting the skin, joints, gastrointestinal tract, and kidneys. The involvement of the penis is rare.

Objective: We aimed to describe this rare manifestation of IgAV/HSP and to review the previous studies, including similar cases.

Methods: Clinical data were reviewed for two children of penile involvement of IgAV/HSP in our hospital. More clinical cases were retrieved from the databases of PubMed/MEDLINE and Scopus from database inception to February 1, 2020.

Results: We presented two boys aged three and five years both of whom had penile lesions after presenting with the typical rash of IgAV/HSP on lower extremities. The penile lesions improved entirely in a few days without treatment in one and with corticosteroid treatment in the other. The literature review revealed 12 articles describing 20 patients with penile involvement of IgAV/HSP. The penile findings were edema, erythema, ecchymosis, purpuric rash, edema, color change, stiffness of the shaft or prepuce, and tenderness. Penile lesions appeared before the purpuric rash of IgAV/HSP in three of 22 patients. The penile involvement could make the diagnosis challenging especially if the penile lesions appear before the typical rash of the disease. The lesions improved entirely in the short term in all patients; in five without treatment in fifteen after corticosteroid or immunosuppressive drug treatment.

Conclusions: It is important to raise awareness about this rare manifestation among health care providers. It is not clear whether corticosteroid treatment should be initiated for treatment since it seems as a self-limited feature. Treatment with corticosteroids could be considered in the treatment of selected cases especially with systemic involvement.
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http://dx.doi.org/10.1016/j.jpurol.2021.01.012DOI Listing
January 2021

Familial Mediterranean fever-related miR-197-3p targets IL1R1 gene and modulates inflammation in monocytes and synovial fibroblasts.

Sci Rep 2021 Jan 12;11(1):685. Epub 2021 Jan 12.

Department of Medical Biology, Hacettepe University, Faculty of Medicine, Ankara, Turkey.

Familial Mediterranean fever (FMF); is an autosomal recessively inherited autoinflammatory disease caused by the mutations in the Mediterranean Fever (MEFV) gene. Recent studies have shown that epigenetic control mechanisms, particularly non-coding RNAs, may play a role in the pathogenesis of autoinflammation. microRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating host gene expression at the post-transcriptional level. The phenotypic heterogeneity of FMF disease suggests that FMF may not be a monogenic disease, suggesting that epigenetic factors may affect phenotypic presentation. Here we examined the potential anti-inflammatory effect of miR-197-3p, which is a differentially expressed miRNA in FMF patients, by using inflammation related functional assays. We monitored gene expression levels of important cytokines, as well as performed functional studies on IL-1β secretion, caspase-1 activation, apoptosis assay, and cell migration assay. These experiments were used to evaluate the different stages of inflammation following pre-miR-197 transfection. Anti-miR-197 transfections were performed to test the opposite effect. 3'UTR luciferase activity assay was used for target gene studies. Our results obtained by inflammation-related functional assays demonstrated an anti-inflammatory effect of miR-197-3p in different cell types (synovial fibroblasts, monocytes, macrophages). 3'UTR luciferase activity assay showed that miR-197-3p directly binds to the interleukin-1beta (IL-1β) receptor, type I (IL1R1) gene, which is one of the key molecules of the inflammatory pathways. This study may contribute to understand the role of miR-197-3p in autoinflammation process. Defining the critical miRNAs may guide the medical community in a more personalized medicine in autoinflammatory diseases.
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http://dx.doi.org/10.1038/s41598-020-80097-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803773PMC
January 2021

Clinical features, muscle biopsy scores, myositis specific antibody profiles and outcome in juvenile dermatomyositis.

Semin Arthritis Rheum 2021 02 22;51(1):95-100. Epub 2020 Dec 22.

Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University, Ankara 06100, Turkey. Electronic address:

Introduction: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy of childhood.

Objective: To analyze clinical features, paraclinical examinations, MSAs, treatment response and long-term outcome in a JDM cohort METHODS: 58 patients (35F, 23 M) from a tertiary referral center in the last two decades are included.

Results: Mean age at onset was 8.1 ± 4.3, with a mean follow-up period of 5.66±3.59 years. Dermatological manifestations (91%) and muscle weakness (76%) were the key diagnostic elements. Elevated serum creatine kinase levels (86%), electromyography (23/25), muscle MRI (12/15), and muscle biopsy (n = 35) were compatible with the diagnosis. Out of 46 patients tested, 34 (76%) had autoantibodies, with NXP2 (21.7%), followed by TIF1g (17.4%), MDA5 (8.7%), and Mi-2 (8.7%). Presence of TIF1g and NXP2 indicated a severe course; and Ku a much severe course compared to previous studies. Corticosteroids (100%) combined with methotrexate (93%) was the initial treatment. Biological disease modifying anti-rheumatic drugs (DMARDs) were used in 22% of the cohort. Calcinosis (36%) was the most common long-term complication, associated with disease onset ≤6 years, higher muscle biopsy scores and MDA5 positivity. Complete remission was achieved in 65.5% of the patients in a median 24 (IQR 11.8-42.5) months with a relapse rate of 26.3%. 43.9% of NXP2 and 33.3% of TIF-1 g positive patients had a relapse. Course was monophasic (31%), polyphasic (17.2%), chronic (51.8%) without mortality.

Conclusion: Integration of clinical features with laboratory and biopsy findings may help to predict prognosis and guide treatment in JDM. In our cohort calcinosis was associated with age, MDA5 autoantibodies, and muscle biopsy scores.
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http://dx.doi.org/10.1016/j.semarthrit.2020.10.007DOI Listing
February 2021

Validation of the EULAR/ACR 2017 idiopathic inflammatory myopathy classification criteria in juvenile dermatomyositis patients.

Clin Exp Rheumatol 2021 May-Jun;39(3):688-694. Epub 2020 Dec 4.

Division of Paediatric Rheumatology, Department of Paediatrics, Hacettepe University, Ankara, Turkey.

Objectives: In 2017, a new set of criteria was proposed by EULAR/ACR to classify idiopathic inflammatory myopathies. Our aim was to validate the EULAR/ACR 2017 classification criteria in juvenile dermatomyositis (JDM) patients.

Methods: This study was carried out at Hacettepe University Children's Hospital Department of Paediatrics, Divisions of Rheumatology, Neurology and Paediatric Pathology Unit. Control patients included inborn errors of metabolism presenting with myopathy and/or rhabdomyolysis, idiopathic rhabdomyolysis, dystrophinopathies, neuromyotonia and systemic rheumatic disorders. Patients' data were collected retrospectively from patient files.

Results: Fifty-eight JDM patients (60.3% female) and 40 controls (32.5% female) were included in this study. When the probability cut-off was set at 55% as recommended, the sensitivity/specificity of the new criteria to diagnose JDM were 96.5%/85% in the total cohort, 95.8%/84.6% without the muscle biopsy data and 97%/85.7% with biopsy data. With the ROC curve analysis, the optimal probability cut-off for the whole cohort was found to be >62%; providing a sensitivity/specificity of 96.6% (95% CI: 88.1% to 99.6)/90% (95% CI: 76.3% to 97.2%), and >68.5% for the patients with muscle biopsy providing sensitivity/specificity of 97% (84.7-99.9%)/100% (76.8-100%), respectively. The new EULAR/ACR criteria were the most sensitive, however, the least specific compared to the Tanimoto criteria (sensitivity/specificity 64%/97.5%) and Bohan-Peter criteria (sensitivity/ specificity 74.1%/92.5%).

Conclusions: The new EULAR/ACR criteria performed favourably in our JDM cohort especially with the probability cut-off of >62%.
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May 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

Pulmonary Manifestations of Systemic Vasculitis in Children.

Pediatr Clin North Am 2021 02;68(1):167-176

Department of Pediatric Rheumatology, Hacettepe University, Sihhiye Campus, Ankara 06100, Turkey. Electronic address:

Vasculitides are defined according to the vessel size involved, and they tend to affect certain organ systems. Pulmonary involvement is rare in the common childhood vasculitides, such as Kawasaki disease, IgA vasculitis (Henoch Schonlein purpura). On the other hand, lung involvement is common in a rare pediatric vasculitis, granulomatosis with polyangiitis (GPA) (Wegener granulomatosis), where respiratory system findings are common. A criterion in the Ankara 2008 classification criteria for GPA is the presence of nodules, cavities, or fixed infiltrates. The adult data suggest that rituximab may be an alternative to cyclophosphamide in induction treatment.
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http://dx.doi.org/10.1016/j.pcl.2020.09.014DOI Listing
February 2021

Performances of the "MS-score" And "HScore" in the diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis patients.

Rheumatol Int 2021 Jan 19;41(1):87-93. Epub 2020 Nov 19.

Department of Pediatric Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Macrophage activation syndrome (MAS) is a devastating complication of systemic JIA (sJIA), seen in approximately 10-25% of the sJIA patients. A number of criteria have been proposed to differentiate between activation of sJIA and MAS, including HScore and the recently proposed MS-score. This is the first study comparing the performances of MS-score and HScore for the diagnosis of MAS in sJIA patients. Systemic JIA patients followed at Hacettepe University Pediatric Rheumatology Unit were included in the study. Clinical features and laboratory findings at the time when the disease was most active or patients were diagnosed with MAS were recorded retrospectively. HScore and MS-score were calculated and the diagnostic performance for MAS was compared by receiver operating characteristic (ROC) curve analysis. Seventy-one sJIA patients were included (23 MAS, 48 activation). There was no difference in age of onset (median 4.7 vs. 5.0 years) and gender (73.9% vs. 54.2%) between patients who had MAS and sJIA activation. Median MS-score and HScore were higher in the MAS group. ROC curve analysis revealed that the HScore performed slightly better in diagnosing MAS, compared with the MS-score (AUC = 0.965 and 0.901 for HScore and MS-score respectively, P < 0.001). In our cohort, the optimal cut-off for the MS score was ≥ - 1.64 (sensitivity: 91.3%; specificity: 83.8%) and for the HScore it was ≥ 162.5 (sensitivity: 91.3%; specificity: 90.2%). HScore performed slightly better than MS-score for the diagnosis of MAS in our cohort.
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http://dx.doi.org/10.1007/s00296-020-04750-xDOI Listing
January 2021

Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency.

Front Immunol 2020 21;11:574738. Epub 2020 Oct 21.

University of South Florida at Johns Hopkins All Children's Hospital, Saint Petersburg, FL, United States.

Vasculitis can be a life-threatening complication associated with high mortality and morbidity among patients with primary immunodeficiencies (PIDs), including variants of severe and combined immunodeficiencies ((S)CID). Our understanding of vasculitis in partial defects in recombination activating gene (RAG) deficiency, a prototype of (S)CIDs, is limited with no published systematic evaluation of diagnostic and therapeutic modalities. In this report, we sought to establish the clinical, laboratory features, and treatment outcome of patients with vasculitis due to partial RAG deficiency. Vasculitis was a major complication in eight (13%) of 62 patients in our cohort with partial RAG deficiency with features of infections and immune dysregulation. Vasculitis occurred early in life, often as first sign of disease (50%) and was complicated by significant end organ damage. Viral infections often preceded the onset of predominately non-granulomatous-small vessel vasculitis. Autoantibodies against cytokines (IFN-α, -ω, and IL-12) were detected in a large fraction of the cases tested (80%), whereas the majority of patients were anti-neutrophil cytoplasmic antibodies (ANCA) negative (>80%). Genetic diagnosis of RAG deficiency was delayed up to 2 years from the onset of vasculitis. Clinical cases with sole skin manifestation responded well to first-line steroid treatment, whereas systemic vasculitis with severe end-organ complications required second-line immunosuppression and/or hematopoietic stem cell transplantation (HSCT) for definitive management. In conclusion, our data suggest that vasculitis in partial RAG deficiency is prevalent among patients with partial RAG deficiency and is associated with high morbidity. Therefore, partial RAG deficiency should be included in the differential diagnosis of patients with early-onset systemic vasculitis. Diagnostic serology may be misleading with ANCA negative findings, and search for conventional autoantibodies should be extended to include those targeting cytokines.
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http://dx.doi.org/10.3389/fimmu.2020.574738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609967PMC
June 2021

The Performances of the ACR 1997, SLICC 2012, and EULAR/ACR 2019 Classification Criteria in Pediatric Systemic Lupus Erythematosus.

J Rheumatol 2020 Nov 15. Epub 2020 Nov 15.

E.D. Batu, MD, MSc, U. Kaya Akca, MD, E. Sağ, MD, S. Demir, MD, Y. Bilginer, MD, MSc, S. Ozen, MD, MSc, Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara; A. Pac Kısaarslan, MD, S. Özdemir Çiçek, MD, H. Poyrazoglu, MD, Department of Pediatrics, Division of Rheumatology, Erciyes University Faculty of Medicine, Kayseri; F. Demir, MD, B. Sozeri, MD, Department of Pediatrics, Division of Rheumatology, Ümraniye Training and Research Center, University of Health Sciences, Istanbul, Turkey. The authors declare no conflict of interest. Address correspondence to Dr. S Özen, Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey. Email: Accepted for publication November 5, 2020.

Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. The American College of Rheumatology (ACR) 1997, Systemic Lupus International Collaborating Clinics (SLICC) 2012, and European League Against Rheumatism (EULAR)/ACR 2019 SLE classification criteria are formed based on data mainly from adult patients. We aimed to test the performances of the SLE classification criteria among pediatric patients with SLE.

Methods: Pediatric patients with SLE (n = 262; 80.9% female) were included from 3 different centers in Turkey. As controls, 174 children (60.9% female) with other diseases who had ANA (antinuclear antibody) test results were included. The gold standard for SLE diagnosis was expert opinion.

Results: The sensitivities of the ACR 1997, SLICC 2012, and EULAR/ACR 2019 criteria were 68.7%, 95.4%, and 91.6%, respectively. The specificities of the ACR 1997, SLICC 2012, and EULAR/ACR 2019 criteria were 94.8%, 89.7%, and 88.5%, respectively. Eighteen patients with SLE met the SLICC 2012 but not the EULAR/ACR 2019 criteria. Among these, hematologic involvement was prominent (n = 13; 72.2%). Eight patients with SLE fulfilled the EULAR/ACR 2019 but not the SLICC 2012 criteria. Among these, joint involvement was prominent (n = 6; 75%).

Conclusion: To our knowledge, this is the largest cohort study of pediatric SLE to test the performances of all 3 classification criteria. The SLICC 2012 criteria yielded the best sensitivity, whereas the ACR 1997 criteria had the best specificity. SLICC 2012 criteria performed better than EULAR/ACR 2019 criteria. Separation of different hematological manifestations in the SLICC 2012 criteria might have contributed to the higher performance of this criteria set.
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http://dx.doi.org/10.3899/jrheum.200871DOI Listing
November 2020

Analysis of polymorphisms in the colchicine binding site of tubulin in colchicine-resistant familial Mediterranean fever patients.

Mol Biol Rep 2020 Nov 7;47(11):9005-9011. Epub 2020 Nov 7.

Department of Medical Biology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Familial Mediterranean fever is a hereditary autoinflammatory syndrome. The typical treatment for the disease is colchicine. However, a subset of patients are not responsive to colchicine. In this study, polymorphisms in the colchicine-binding site of the TUBB1 gene, which encodes a tubulin isoform specific to leukocytes, were investigated in patients with colchicine-resistant disease. FMF patients who were followed in the Department of Pediatric Rheumatology at Hacettepe University were included in this study. Colchicine resistance was defined as ongoing disease activity (≥ 1 attack/month over 3 months or persistently elevated CRP) while taking the maximum tolerated dose of colchicine. A total of 62 Turkish FMF patients (42 colchicine-responsive and 20 colchicine-resistant) and a control group of healthy children were included in the study. DNA was extracted for analysis of TUBB1, and the colchicine binding site was sequenced. We did not observe A248T (rs148237574) or M257V (rs759579888), two variations that were previously associated with colchicine resistance in an in silico analysis. We did detect T274M (rs35565630), R306H (rs772479017), and R307H (rs6070697) variants in the FMF patients, but there was no statistically significant difference between the colchicine-responsive and colchicine-resistant groups. This is the first study to evaluate TUBB1 gene polymorphisms in the colchicine binding site in patients with FMF. Our data do not support the hypothesis that these polymorphisms are a possible cause of colchicine resistance in FMF patients.
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http://dx.doi.org/10.1007/s11033-020-05957-8DOI Listing
November 2020