Cold-induced Vascular Changes in the Macula, Optic Disc and Choroid in Children with Raynaud's Phenomena.

AIM: To investigate changes in retinal and choroidal vessels in children with primary and secondary raynaud's phenomena(RP). METHODS: Measurements were performed by optic coherence tomography angiography before as well as during and 10 minutes after the immersion of one hand in ice water. RESULTS: Primary RP patients exhibited enlargement of the foveal avascular region and decrease in vessel density in the parafoveal superficial capillary plexus (SCP) during cold exposure, but values returned to normal when the hands were removed from the cold water. In children with secondary RP, there were decreases in choroidal thickness and vessel density in the SCP and radial peripapillary capillary plexus (RPCP) during cold exposure. Changes in choroid and peripapillary RPCP were still significant 10 minutes after removal from cold water. CONCLUSION: Ocular arteriolar vasospasm seems to be more pronounced in patients with secondary RP, particularly in the choroid and the peripapillary area of the RPCP. CLINICAL TRIAL REGISTRATION NUMBER AND DATE: DECISION NUMBER: 76/1315 - 10.03.2021.

Experience of Autoimmune and autoinflammatory diseases in a Turkish pediatric cohort with primary immunodeficiencies.

BACKGROUND: Primary immunodeficiency diseases (PID) are the diseases characterized by a dysfunction of the immune system. Affected patients share a different phenotype such as chronic infections, allergy, autoimmunity, and autoinflammation. METHODS: In all, 433 children with PID were enrolled in this study. Clinical, laboratory, and demographic data of patients were reviewed retrospectively to investigate autoimmune and autoinflammatory complications. Autoinflammation in all patients with inflammation was confirmed by genetic analysis after excluding infectious etiology. RESULTS: Clinical features of 433 PID patients were evaluated retrospectively with long-term follow-up. Autoimmune disorders were identified in 69 (15.9%) patients with PID; 31 (45%) patients had a history of autoimmune disease before diagnosis of PID. The frequency of autoimmunity in immune dysregulation subgroup (76.6%) was higher than other forms of PID. The most common autoimmune manifestations were reported to be Addison's disease, hypoparathyroidism, and autoimmune hemolytic anemia. Autoinflammation were identified in 22 of the 433 (5.1%) patients with PID, including hyper immunoglobulin D syndrome (n = 9), Aicardi-Goutieres syndrome 1 (n = 6), adenosine deaminase 2 deficiency (n = 3), Blau syndrome (n = 2), tumor necrosis factor (TNF) receptor-associated periodic syndrome (n = 1), and auto-inflammation and phospholipase Cγ2-associated antibody deficiency and immune dysregulation syndrome (n = 1). CONCLUSIONS: It is important to recognize association between autoimmunity, autoinflammation, and PID, which in the future could be useful for increased awareness and early diagnosis for these diseases.

Clinical features of childhood uveitis at a tertiary referral center in Southern Turkey.

PURPOSE: To report the epidemiology, etiology, ocular characteristics, management, and visual outcomes of pediatric uveitis patients in Southern Turkey. METHODS: The clinical records of pediatric patients with a diagnosis of uveitis under the age of 16 years and followed up longer than 6 months were analyzed retrospectively. RESULTS: The study included 102 patients and 173 affected eyes. The mean age at presentation was 11.4 ± 3.7 years. Uveitis was predominantly bilateral (69.6%), anterior (45.1%), and chronic (58.8%). The leading diagnoses were idiopathic uveitis (38.2%), pars planitis (19.6%), and juvenile idiopathic arthritis-associated uveitis (14.7%). Infectious uveitis accounted for 12.7%, and toxoplasmosis was the most common cause (10.8%). At least one complication was observed in 76.3% of the eyes, and optic disk edema (37%) was the most frequent. Corticosteroids were used in 97.1% and systemic immunomodulatory agents in 49% of the patients. Ocular surgery was performed in 17.3% of the eyes, and cataract extraction was the most common (8.7%). The mean BCVA was 0.39 ± 0.66 LogMAR at baseline and 0.25 ± 0.53 LogMAR at the last recorded visit. CONCLUSION: Pediatric uveitis is a challenging disease that requires meticulous management. Anterior uveitis is the most frequent form. Despite a changing trend for an increase in diagnostic variety, idiopathic cases still constitute the majority. A significant number of patients receive systemic therapy, develop complications, and require surgical intervention. Early diagnosis and appropriate treatment might improve visual outcomes and reduce the risk of visual loss.

Serum lubricin levels in patients with juvenile idiopathic arthritis.

OBJECTIVES: Lubricin, encoded by the proteoglycan 4 (PRG4) gene, is mainly responsible for lubricating joints. However, there is expanding evidence on its involvement in inflammatory pathways. Juvenile idiopathic arthritis (JIA) is a heterogeneous group of chronic arthritides with an unknown origin in children aged below 16 years. It is characterized by chronic joint inflammation, including synovial inflammation, and may result in cartilage destruction. We aimed to determine whether serum lubricin levels are affected in JIA patients. MATERIAL AND METHODS: This cross-sectional study included children diagnosed with JIA and 28 healthy controls. The patients were divided into two groups according to the presence of remission at the time of study. Lubricin protein analysis was performed by the enzyme-linked immunosorbent assay method. Serum samples were obtained at the study enrollment, and lubricin levels were measured once, and compared between JIA patients and healthy controls, and between JIA patients with active disease and remission. RESULTS: The study included 52 JIA patients (28 female, 24 male) and 28 healthy controls (18 female, 10 males). The mean age at study enrollment was 11.66 ±4.41 years and 12.72 ±4.52 years in the JIA patient and control groups, respectively. Although median serum lubricin level did not differ between JIA patients (median: 0.66 ng/µl, range: 0.02-3.85 ng/µl) and healthy controls (median: 0.52 ng/µl, range: 0.06-3.84 ng/µl), it was statistically significantly higher in patients with active disease (median: 1.58 ng/µ, range: 0.08-3.85 ng/µl) than both patients in remission (median: 0.57 ng/µl, range: 0.02-3.57 ng/µl) and healthy controls. A low degree positive correlation was also found between serum lubricin levels and erythroid sedimentation rate of the JIA patients (r = 0.383 and p = 0.011). CONCLUSIONS: This is the first study investigating serum lubricin levels in JIA patients, and we found elevated serum lubricin levels in JIA patients with active disease. Further studies are needed to clarify our results.

Evaluation of different classification criteria in children with Behcet disease: results from a single referral center.

OBJECTIVES: Behcet Disease (BD) is a systemic vasculitis, first described with a triad of oral aphthous ulcers, genital ulcers, and uveitis. The authors aimed to share the clinical properties and utilities of three distinct classification criteria for BD in this study. METHODS: This case-control study was conducted in pediatric BD patients, diagnosed between January 2012 and July 2019. The control group included 53 children with other rheumatic disorders. Sensitivity and specificity for International Study Group (ISG), International Criteria for BD (ICBD), and pediatric criteria for BD (PEDBD) criteria were tested. RESULTS: The mean age at symptom onset and diagnosis of the 16 BD patients (6 females, 10 males) were 11.2 ± 3.6 and 13 ± 3.1 years, respectively. The sensitivity and specificity of ISG criteria were 87.5% and 100%. Furthermore, ICBD criteria had a sensitivity and specificity of 93.7% and 98.1%, whereas the authors found sensitivity and specificity as 93.7% and 96.2% for PEDBD. CONCLUSION: ICBD and PEDBD reached higher sensitivity for pediatric BD diagnosis and ICBD had the highest specificity. The authors speculate that the utilization of ICBD may provide early diagnosis of BD in childhood, prevent related morbidities and misdiagnosis.

Growth Parameters of Turkish Children With an Autoinflammatory Disease Before and After Canakinumab Treatment.

OBJECTIVE: To evaluate the effect of canakinumab on growth parameters of patients with autoinflammatory diseases. METHODS: This retrospective study included Colchicine resistant familial Mediterranean fever (FMF), Mevalonate kinase deficiency (MKD), Tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), Deficiency of adenosine deaminase 2 (DADA2) patients treated with canakinumab for at least six consecutive months. RESULTS: Eleven patients with FMF, 9 with MKD, 3 with TRAPS, and 1 with DADA2 were included. The median age (range) at diagnosis and drug initiation was 6.06 (1.45-16.06) years and 9.72 (1.82-19.11) years, respectively. The mean weight, height, and BMI SD scores significantly increased after canakinumab. There were significant improvements in laboratory parameters and disease activities. However, growth parameters after the drug did not differ according to gender, the duration of diagnostic delay, and age at the diagnosis. CONCLUSIONS: Canakinumab seems to have a positive effect on growth in patients with autoinflammatory diseases by controlling disease activity and inflammation.

The contribution of diet preference to the disease course in children with familial Mediterranean fever: a cross-sectional study.

OBJECTIVES: Familial Mediterranean fever (FMF) is characterized by recurrent, self-limiting attacks of fever and serositis. Nutrition is very important in the management of chronic diseases. Previous studies suggested that salty and fatty diet cause inflammation, therefore we aimed to investigate the effects of dietary self-efficacy and behavior about low-salt or low-fat diet on disease course in children with FMF. MATERIAL AND METHODS: This cross-sectional study included patients aged between 10-18 years, diagnosed in our department and admitted between June 2019 and September 2019. Demographic and clinical properties were obtained from the medical files of the patients. Children's Dietary Self-Efficacy Scale (CDSS) and Health Behavior Questionnaire (HBQ) - Diet Behavior Scale (DBS) were performed for dietary self-efficacy and behavior about preferring low-salt or low-fat diet. Clinical features were compared between patients, which were grouped according to the sum of these two scales, with a cut-off score of 5. RESULTS: The mean age of 74 FMF patients (44 females, 34 males), included in the study, was 14.6 ±2.82 years. Median CDSS and DBS scores of the patients were 5 (minimum -6, maximum 14) and 0 (minimum -10, maximum 12), respectively. According to the sum of these two scales, 39 (52.7%) patients who had scored at least 5, had a statistically higher rate of complete response to colchicine. The remaining clinical parameters were similar between these two groups. CONCLUSIONS: Low-salt or low-fat diet may be an adjuvant modification in the management of children with FMF. Further studies are needed to clarify the role of low-salt or low-fat diet in FMF pathogenesis.

Retrospective analyzes of adverse events during biologic agents in children with juvenile idiopathic arthritis from a single center in Turkey.

OBJECTIVES: Juvenile idiopathic arthritis is the most common rheumatic disease in childhood. Biologic agents have changed the course of juvenile idiopathic arthritis. However, there are concerns regarding the occurrence of serious adverse events in patients receiving biologic agents. The aim of this study was to evaluate adverse events in children with juvenile idiopathic arthritis receiving biologic agents. MATERIAL AND METHODS: This retrospective study includes juvenile idiopathic arthritis patients receiving biologic agents. Demographic features and adverse events during biologic agents were collected from medical files. Adverse events that either resulted in death, were life-threatening, required inpatient hospitalization, or resulted in persistent or significant disability/incapacity were considered as serious adverse events. RESULTS: In total, 162 juvenile idiopathic arthritis patients (55.6% female) receiving biologic agents were enrolled: 101 (62.3%) patients treated with etanercept, 27 (16.7) with tocilizumab, 14 (8.6%) with adalimumab, 15 (9.2%) with anti-interleukin 1 agents (13 canakinumab, 2 anakinra), and 5 (3.1%) with infliximab. 75.9% of the patients received concomitantly disease-modifying anti-rheumatic drugs, and 20.4% received disease-modifying anti-rheumatic drugs plus corticosteroid. The mean age at initiation of the biologic agent was 10.5 ±4.3 years. The mean age at the study enrolment was 12.1 ±4.5 years. The mean follow-up duration was 19.7 ±2.1 months. The most frequent adverse event was upper respiratory tract infections (54.3%) followed by urinary tract infections (21%). Anaphylaxis occurred in 3 patients (1.9%): 2 with tocilizumab and one with infliximab. Macrophage activation syndrome occurred in 1 patient (0.6%) receiving tocilizumab. Lung tuberculosis developed in 2 patients (1.2%) receiving canakinumab. The frequency of serious adverse events in total was 6.7%. CONCLUSIONS: While the most frequent adverse events during biologic agents was upper respiratory tract infections, the frequency of serious adverse events was 6.7%; therefore, juvenile idiopathic arthritis patients receiving biologic agents should be carefully evaluated for these adverse events in clinical practice.

Baricitinib experience on STING-associated vasculopathy with onset in infancy: A representative case from Turkey.

Stimulator of interferon genes associated vasculopathy with onset in infancy (SAVI), caused by heterozygote gain-of-function mutations in TMEM173, is characterized by fever attacks with ulcerating cutaneous manifestations on cold-sensitive areas and interstitial lung disease. A six-month-old boy was admitted to our hospital with fever, cough, and rash on the external surface of both upper and lower extremities. Respiratory symptoms consistent with ILD developed and skin lesions evolved to eschar formation particularly on acral regions. Ultimately, diagnosis of SAVI was confirmed at the age of 10 months due to the high level of interferon-score and a heterozygous N154S mutation in TMEM173. Since systemic corticosteroid and ruxolitinib were not effective, baricitinib was initiated at the age of 15 months, resulting in alleviation of fever attacks, cutaneous manifestations and respiratory symptoms within 2 months. In conclusion, we reported an infant diagnosed with SAVI at the age of 10 months and treated with baricitinib.

Clinical manifestations and outcomes of 420 children with Henoch Schönlein Purpura from a single referral center from Turkey: A three-year experience.

Objectives: Henoch Schönlein Purpura (HSP) is the most common systemic vasculitis in childhood. We aimed to evaluate the clinical features, seasonal variation, treatment outcomes and the possible predicting factors related to outcome among a large cohort of pediatric HSP patients.Methods: We conducted a medical record review study between July 2016 and January 2019 and evaluated the clinical manifestations and potential risk factors for severe gastrointestinal (GI) involvement, biopsy-proven nephritis and relapses.Results: The study included 420 HSP patients, of which the mean age at diagnosis was 7.68 ± 3.15 years. Clinical manifestations were arthralgia and/or arthritis (n = 244, 58.1%), abdominal pain (n = 235, 56%), subcutaneous edema (n = 163, 38.8%), and renal involvement (n = 125, 29.8%). Disease recurred for at least once, in 69 (16.4%) patients and colchicine treatment yielded a favorable response in 11 of 12 relapsing patients, who did not respond to ibuprofen or steroids. Frequencies of renal involvement and biopsy-proven nephritis were higher in patients with severe GI involvement. Besides, patients with biopsy-proven nephritis had higher rates of abdominal pain, intussusception, severe GI involvement, and systemic steroid administration.Conclusion: We speculate that renal involvement, biopsy-proven nephritis and severe GI involvement can be related to each other. Colchicine may be effective in patients with relapsing disease.

A homozygote novel L451W mutation in CECR1 gene causes deficiency of adenosine deaminase 2 in a pediatric patient representing with chronic lymphoproliferation and cytopenia.

Deficiency of Adenosine Deaminase 2 (DADA2) is a monogenic autoinflammatory disorder characterized by livedo reticularis, skin ulcers, subcutaneous rash, aphthous ulcers, and leukocytoclastic vasculitis, neurological signs such as early onset stroke and polyneuropathy. A minority of DADA2 patients suffer from severe cytopenia and lymphoproliferation. Herein, we report an adolescent patient, followed up as having a hematological disorder for many years, eventually diagnosed as having DADA2. In view of the presence of elevated acute phase reactants, hepatosplenomegaly, low IgM level, lymphopenia, anemia, and neutropenia, and a subtle neurological involvement we considered DADA2 diagnosis. The diagnosis was confirmed by identification of a novel L451W mutation in CECR1 gene. The patient has been successfully treated with etanercept, monthly intravenous immunoglobulin replacement, and low-dose methylprednisolone. In conclusion, although the absence of skin and neurological findings, low IgM levels, and persistent lymphopenia should lead the physicians to consider DADA2 in patients with particularly complicated hematological abnormalities.

Symptomatic multifocal avascular necrosis in an adolescent with neuropsychiatric systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by malar rash, oral ulcers, arthralgia, photosensitivity and nephritis. Herein, we report a rare comorbidity, multiple avascular necrosis (AVN), in an adolescent SLE patient and also highlight the importance of risk factors for this comorbidity with a brief literature review. A 13-year-old female patient was admitted with severe headache, visual plus auditory hallucinations, polyarthritis and a history of recurrent oral ulcers. Acneiform malar rash, arthritis, cytopenia, low complement levels and autoantibody positivity yielded SLE diagnosis. We diagnosed her as having multifocal AVN after the 4th dose of cyclophosphamide, with bilateral knee pain and swelling and typical geographical lesions on magnetic resonance imaging. Avascular necrosis is a rare comorbidity of SLE and neuropsychiatric involvement, cyclophosphamide administration and severe disease may be the possible risk factors in addition to corticosteroid use. Further multicenter studies investigating the possible risk factors of AVN with a large number of patients are needed.

Do practical laboratory indices predict the outcomes of children with Henoch-Schönlein purpura?

Objectives: Henoch Schönlein Purpura (HSP) is the most common systemic vasculitis of childhood and often has a self-limiting course. We aimed to study whether practical laboratory parameters at the diagnosis predict disease course including recurrence and nephritis in addition to severe gastrointestinal involvement in children with HSP. Methods: This retrospective cohort study included 214 HSP patients, 43.5% (n = 93) female and 56.5% (n =121) male, who were diagnosed in our department. Laboratory parameters before treatment, including neutrophil, lymphocyte and platelet counts, mean platelet volume (MPV), neutrophil-to-lymphocyte (NLR), and platelet-to-lymphocyte ratios (PLR) were obtained retrospectively. Age at diagnosis, duration of follow-up, gender, preceding infections, medications, arthritis and arthralgia, abdominal pain, severe GI involvement, invagination, renal involvement and presence of nephritis, outcomes, and presence of recurrences were retrospectively recorded from medical files. Severe GI involvement was determined as severe colicky abdominal pain, bowel edema in ultrasonography or overt GI bleeding. A relapse was defined as a new flare of cutaneous lesions or other manifestations in a patient at least four asymptomatic weeks after the initial HSP episode. Results: Mean age at diagnosis was 7.6 ± 3.1 years. Biopsy-proven nephritis was found in 16 (7.5%) patients. Severe GI involvement was present in 77 (36%) patients, whereas only 12 (5.6%) patients were diagnosed with intussusception and in 29 (13.5%) patients, HSP recurred. Neutrophil count and NLR were found higher in HSP patients with severe gastrointestinal involvement and biopsy-proven nephritis. Additionally, only platelet count was lower and MPV was higher in patients with recurrent HSP. Conclusion: Elevated neutrophil count and NLR may be relevant markers for severe GI involvement and nephritis, whereas platelet count and MPV were the only laboratory parameters associated with disease recurrence.

Frequency of functional gastrointestinal disorders in children with familial Mediterranean fever.

INTRODUCTION: Familial Mediterranean fever (FMF) is characterized by self-limiting fever episodes usually accompanied by serositis, arthralgia, and arthritis. Functional gastrointestinal disorders (FGIDs) are diseases in which brain-gut axis and low-grade inflammation take part in pathogenesis. We aimed to study the FGIDs frequencies and possible risk factors for FGIDs in children with FMF. METHOD: This case-control study included 103 children with FMF followed up between July 2016 and July 2018 and 100 healthy controls. Age, gender, disease characteristics, and MEFV gene results were recorded retrospectively. Laboratory parameters were obtained at the time of study enrollment. Diagnosis of FGIDs was assessed with Rome IV criteria. RESULTS: The mean age at study enrollment was 12.58 ± 3.79 and 9.71 ± 3.59 years in FMF and healthy control groups, respectively. Overall FGID frequency was 39.8% (n = 41) in FMF patients and 19% (n = 19) in the control group. Functional dyspepsia and irritable bowel syndrome (particularly constipation predominant subtype) rates were statistically higher in the FMF group. In detail, genotype, age at onset, symptoms, colchicine duration, and colchicine responses did not differ between FMF patients in regard to having FGIDs. CONCLUSIONS: This study showed that children with FMF may predispose to pain predominant FGIDs. We also suggest that FGIDs should be considered in FMF patients suffering recurrent abdominal pain episodes unaccompanied by APR elevation, which can be also named as incomplete FMF attacks.

Juvenile systemic lupus erythematosus: a single-center experience from southern Turkey.

OBJECTIVES: This study was conducted to analyze clinical characteristics, laboratory data, disease activity, and outcome of juvenile systemic lupus erythematosus (jSLE) patients from southern Turkey. METHODS: Fifty-three patients with jSLE diagnosed according to the revised American College of Rheumatology 1997 criteria between January 2005 and June 2018 were included in the present study. RESULTS: The median age at the diagnosis was 12.8 (range, 5.1-17.7) years. The female to male ratio was 9.6:1. The most prevalent clinical features were mucocutaneous involvement (96.2%) and constitutional manifestations (94.3%). Renal manifestations, hematological manifestations, and neuropsychiatric involvement were detected in 40 (75%), in 38 (71.7%), and in 13 (24.5%) patients, respectively. Renal biopsy was performed to 49 patients (92.5%). Class IV lupus nephritis (LN) (34%) and class II LN (20.4%) were the most common findings. Mycophenolate mofetil, cyclophosphamide with corticosteroid were the main treatment options. Eighteen patients received rituximab and one tocilizumab. The mean SLE Disease Activity Index (SLEDAI) score at the time of diagnosis was 22.47 ± 8.8 (range = 3-49), and 1.34 ± 1.85 (range = 0-7) at last visit. Twenty-one patients (39.6%) had damage in agreement with Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (PedSDI; mean = 0.60 ± 0.94; range = 0-5) criteria. Growth failure was the most prevalent cause of damage (n = 13, 26%). One patient deceased due to severe pulmonary hemorrhage and multiple cerebral thromboses. CONCLUSION: jSLE patients in this cohort have severe disease in view of the higher frequency of renal and neurologic involvement. Nevertheless, multicenter studies are needed to make a conclusion for all Turkish children with jSLE.

MEFV gene variants in children with Henoch-Schönlein purpura and association with clinical manifestations: a single-center Mediterranean experience.

OBJECTIVES: Henoch-Schönlein purpura (HSP) is characterized by non-thrombocytopenic palpable purpura, abdominal pain, and arthralgia/arthritis. We aimed to describe the clinical presentations of children with HSP in a single center and compare the prevalence of each manifestations between patients with MEFV variants, particularly in exon 10 and those without. METHODS: This cohort retrospectively included 144 HSP (59 females, 85 males) patients without Familial Mediterranean Fever (FMF) symptoms and followed for at least 6 months. We utilized the MEFV gene sequencing by using next-generation sequencing platform (MiSeq System, Illumina). RESULTS: At least one MEFV variant was detected in 73 (50.7%) of 144 HSP patients and 5 (3.5%) patients were homozygote for M694V mutation. Although severe gastrointestinal involvement and nephritis rates were similar, we found that serum IgA, leukocyte, and platelet count at diagnosis were higher and hemoglobin was lower in HSP patients with MEFV gene variants in exon 10 than those without. Additionally, HSP patients with MEFV variants in exon 10 more often present with abdominal pain and intussusception. CONCLUSION: MEFV variants in exon 10 may affect clinical presentation of HSP in populations where FMF is common. While HSP may be an initial symptom of FMF, we speculate that physicians should be aware of FMF possibility in children with intussusception and lower hemoglobin, higher serum IgA, leukocyte, and platelet count.

Decreased serum vitamin B12 and vitamin D levels affect sleep quality in children with familial Mediterranean fever.

Familial Mediterranean fever is an autoinflammatory disorder characterized by recurrent fever and serositis. We aimed to describe serum vitamin B12 and vitamin D levels and their correlation with self-reported sleep quality of pediatric FMF patients. Sixty-three children with FMF were enrolled to the study. Information on sleep quality was obtained using self-administration of Pittsburg Sleep Quality Index (PSQI). The patients were divided into subgroups depending on vitamin D serum concentrations: ≥ 20 and < 20 ng/ml. We also grouped patients according to their serum B12 concentration: ≥ 200, < 200 pg/ml. B12 levels were not correlated with PSQI scores, whereas significant correlation was found between vitamin D and total PSQI scores and daytime sleepiness. Total PSQI score, sleep disorders and daytime sleepiness sub-scores were statistically high in patients with serum D vitamin levels below 20 ng/ml. Sleep efficiency was found lower in patients with serum B12 levels below 200 pg/ml. B12 may have a positive role on effective sleep. More importantly, we suggest that vitamin D is protective against sleep disorders and poor sleep, it may also improve daytime activities.