The assessment of fatigue and sleep quality among children and adolescents with familial Mediterranean fever: A case-control and correlation study.

To evaluate the sleep quality and fatigue levels in children with familial Mediterranean fever (FMF) in comparison to healthy children. The Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL-MFS) and the Pittsburgh Sleep Quality Index (PSQI) were the instruments utilized to assess fatigue and sleep quality in children with FMF and controls, respectively. Spearman's rank coefficient was decisive in determining the association between patient-reported outcome measures and disease-related features. Two hundred twenty-five (59.3% female) patients and 182 (51.6% female) healthy counterparts were enrolled in the study. In PSQI, where high scores indicate sleep disturbance, the median score was significantly higher in the patient group (5; 3-6) than the control group (3; 2-4) (p < 0.001). PEDsQL-MFS demonstrated significantly lower fatigue levels in the control group than patients (p = 0.01). The level of fatigue in the patient group was found to increase in correlation with sleep problems (r: - 0.750, p < 0.001). Additionally, a high correlation was present between the PSQI/PedsQL-MFS scores and the number of attacks in the last year (r: - 0.645, p < 0.001/r: 0.721, p < 0.001, respectively). There was no difference in terms of fatigue and sleep disorders between mutations (homozygous, heterozygous, or compound heterozygous) in the MEFV gene (p > 0.05).    Conclusion: High disease activity has a significant negative impact on the sleep quality and fatigue levels of patients with FMF. This study emphasizes the importance of assessing fatigue and sleep quality with objective outcome tools periodically in FMF patients throughout the disease course. What is Known: • Fatigue is a common matter that often accompanies rheumatic diseases and causes disability. • Chronic rheumatic diseases often experience poor sleep quality. What is New: • In high correlation with the disease severity of familial Mediterranean fever, sleep quality decreases and fatigue level increases significantly. • In familial Mediterranean fever patients, a negative correlation is present between age and the general fatigue and sleep/rest related fatigue scores (low scores indicating greater fatigue) and sleep quality is poorer in the adolescent age group.

Ovarian reserve in children with juvenile idiopathic arthritis using biologic disease-modifying anti-rheumatic drugs.

BACKGROUND/OBJECTIVES: The aim of the study is to assess the effect of juvenile idiopathic arthritis (JIA) and biologic disease-modifying anti-rheumatic drugs (bDMARDs) on ovarian reserve in children. MATERIALS AND METHODS: A cross-sectional study was performed from March 2021 to March 2022 and included 81 patients with JIA and 49 healthy children. Serum anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol levels were analyzed using electrochemiluminescence methods. RESULTS: The mean of current age (13.5 ± 3.2 vs. 14.4 ± 2.4 years), height standard deviation score (SDS) (- 0.35 ± 1.18 vs. - 0.44 ± 0.94), body mass index SDS (0.12 ± 1.33 vs. 0.25 ± 1.28), and the median weight SDS (- 0.13 (- 2.27-3.23) vs. - 0.52 (- 3.4-3.3)) were similar in JIA patients and controls (p > 0.05). Patients with JIA were divided into two groups according to their treatment regimens: treated with methotrexate (MTX) (biologic naive) (n = 32) and treated with MTX plus bDMARDs (n = 49). No significant differences were detected between the 3 groups regarding menarche age, menstrual cycle length, and flow duration (for all p > 0.05). The median serum concentration of AMH was 2.94 (1.12-7.88) ng/ml in the control group, 3.02 (0.36-8.54) ng/ml in the biologic naïve group, and 3.01 (0.99-8.26) ng/ml in the MTX plus bDMARD group. There were no significant differences between 3 groups according to serum AMH, FSH, LH, and estradiol levels (p > 0.05). CONCLUSION: Biologic DMARDs are reassuring in terms of ovarian reserve in girls with JIA and demonstrate that AMH is unaffected by treatment. Prospective studies with larger sample sizes are needed to confirm our findings and to evaluate the impact on the future fertility of patients. Key Points • Although biologic disease-modifying anti-rheumatic drugs (bDMARDs) are being game-changing treatment options in juvenile idiopathic arthritis, their effect on fertility and ovarian reserve is one of the most discussed issues. • In addition to treatment used, autoimmune diseases might also have a negative effect on fertility. • In this cross-sectional study, we found that anti-Mullerian hormone level of patients who were on bDMARDs, patients who were on methotrexate, and healthy controls were similar. • Our results suggest that bDMARDs are reassuring in terms of ovarian reserve in girls with JIA and demonstrate that AMH is unaffected by treatment.

Comparison of EULAR/PRINTO/PReS Ankara 2008 and 2022 ACR/EULAR Classification Criteria for Granulomatosis with Polyangiitis in Children.

OBJECTIVE: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic antibody-associated vasculitis. The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR)-endorsed classification criteria for GPA was derived using data only from adult patients. We aimed to assess the performance of the ACR/EULAR classification criteria for GPA in pediatric patients and compare it with the EULAR/Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology European Society (PReS)-endorsed Ankara 2008 criteria for GPA. METHODS: Retrospective data of pediatric patients with GPA in 20 centers from 9 countries were evaluated. The diagnosis of GPA was made according to the expert opinion. The sensitivity, specificity, positive predictive value, and negative predictive value of the criteria sets were evaluated. RESULTS: The study included 77 patients with GPA and 108 controls (immunoglobulin A vasculitis (n = 44), Takayasu's arteritis (n = 20), microscopic polyangiitis (n = 16), polyarteritis nodosa (n = 14), Behçet's disease (n = 12), eosinophilic granulomatosis with polyangiitis (n = 1), and Cogan's syndrome (n = 1)) with a median age of 17.8 and 15.2 years, respectively. Of patients with GPA, constitutional symptoms (85.7%) and ear-nose-throat involvement (79.2%) were the most common presentations. In the GPA group, 73 patients fulfilled the Ankara 2008 criteria and 69 the ACR/EULAR classification criteria. Sensitivities of the Ankara 2008 criteria and the ACR/EULAR classification criteria were 94.8% and 89.6%, while specificities were 95.3% and 96.3%, respectively. No significant difference was found between sensitivities and specificities of both classification criteria (p= 0.229 and p= 0.733, respectively). CONCLUSION: In children, both the ACR/EULAR and EULAR/PRINTO/PReS Ankara 2008 classification criteria for GPA perform well and similarly.

The impact of COVID-19 on clinical course and treatment among patients with juvenile systemic sclerosis.

Objectives: This study aimed to explore the influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic among patients with juvenile systemic sclerosis (JSS). Patients and methods: Twenty-seven patients (22 females, 5 males; mean age: 20 years; range, 17 to 22 years) diagnosed with JSS and followed up at the department of pediatric rheumatology were included in the cross-sectional study. A web-based survey was performed by focusing on patients' complaints, accessibility to health care, and compliance with routine treatment from January 1, 2021, to January 10, 2021. Results: Five (18.5%) patients had deterioration of the disease, while six (22.2%) patients reported irregular usage of their routine scleroderma treatment during the last six months. Nine (33.3%) patients had missed their routine clinic control since the proclamation of the SARS-CoV-2 pandemic. Seven (25.9%) patients had household contact with coronavirus disease 2019 (COVID-19). Four (14.8%) patients were diagnosed with COVID-19, and only one (3.7%) was hospitalized. Nine patients were under biological treatment (tocilizumab); however, only one of them was diagnosed with COVID-19. Conclusion: The COVID-19 pandemic has not significantly disrupted the medical care of JSS patients. Telemedicine could be an acceptable option for JSS patients disenabled to come to the hospital.

Clinical features, treatment and outcome of pediatric patients with severe cutaneous manifestations in IgA vasculitis: Multicenter international study.

OBJECTIVE: IgA vasculitis (IgAV) (formerly Henoch-Schönlein Purpura, HSP) rarely causes severe skin lesions in children. The purpose of the research was to determine whether severe skin manifestations were associated with a more severe disease course. METHODS: Severe cutaneous manifestations were defined as presence of hemorrhagic vesicles, bullae, ulcerations and/or necroses. Data were collected retrospectively from 12 international tertiary university medical centers. RESULTS: A total of 64 patients with the most severe skin changes in IgAV/HSP and median (Q1, Q3) age of 8.08 (5.08, 11.92) years at the disease onset were compared with 596 IgAV/HSP patients without these manfiestations and median (Q1, Q3) age of 6.33 (4.50, 8.92) years. The patients with severe cutaneous manifestations were older in comparison to other patients with IgAV/HSP (p<0.001), they developed nephritis more frequently (40.6% vs. 20.6%, p = 0.001) with worse outcome of renal disease (p = 0.001). This group of patients also had higher frequencies of severe gastrointestinal complications like hematochezia, massive bleeding and/or intussusception (29.3% vs. 14.8%, p<0.001). d-dimer concentrations were significantly higher in these patients (4.60 mg/L vs. 2.72 mg/L, p = 0.003) and they had more frequent need for treatment with systemic glucocorticoids (84.4% vs. 37.2%, p<0.001) in comparison with the control group. Further multivariate analysis showed that severe cutaneous changes were associated with higher risk of developing nephritis [OR=3.1 (95%CI 1.04-9.21), p = 0.042] and severe gastrointestinal complications [OR=3.65 (95%CI 1.08-12.37), p = 0.038]. CONCLUSION: Patients with IgAV/HSP and severe skin manifestations had a more severe clinical course and more frequently required glucocorticoids compared to classic IgAV/HSP patients.

Reply to comment by Kao et al on "An overview of the relationship between juvenile idiopathic arthritis and potential environmental risk factors: Do early childhood habits or habitat play a role in the affair?"

In our study, in which the relationship between juvenile idiopathic arthritis (JIA) and particular environmental factors was evaluated, a correlation could not be established between the rate or duration of breastfeeding and the development or severity of the disease. Int J Rheum Dis, 25, 2022, 1376. It was determined that the time of introduction to cow's milk differed in JIA and juvenile-onset systemic lupus erythematosus patient groups compared to healthy controls. On the other hand, the fact that income level and maternal literacy were associated with high disability and damage scores and frequent recurrence rates stood as one of the remarkable results of our study. Kao et al drew attention to the relationship between socioeconomic status and chronic arthritis and quoted an adult study. The role of the parent factor has been stressed and the effect of maternal stress on disease development has been discussed. Although JIA is a heterogeneous disease and the tribulation of measuring the direct impact of environmental elements are limiting factors, it is essential to determine the parts that can be controlled to some extent and the precautions to be taken.

Autoimmune and autoinflammatory diseases with mucocutaneous manifestations: A pediatric rheumatology perspective.

The presence of mucocutaneous manifestations has clinical significance, as it may be a part of the initial presentation or activation stage of both autoimmune and autoinflammatory rheumatic diseases. The cutaneous signs may display a particular morphological and topographic distribution according to taxonomy, whereas heterogeneity is likely observed among the individuals. The review aims to cluster and systematically approach the mucocutaneous manifestations met in autoimmune and autoinflammatory rheumatic diseases of childhood. The search strategy involved a comprehensive inquiry on Web of Science, PubMed, MEDLINE, and Embase databases using relevant search terms such as "dermatologic, cutaneous, mucocutaneous, skin, rash" for each disease and category. The awareness of the distinctive mucocutaneous manifestations and their correlation with rheumatic diseases provides a convenient definition, well-timed control of the underlying condition, and prevention of cosmetic issues. In the management of rheumatic diseases, planning the pertinent differential diagnosis and determining the requirement of histopathological assessment are essential with a multidisciplinary approach to rheumatology, dermatology, and allergy-immunology specialties.

Performance of recent PRINTO criteria versus current ILAR criteria for systemic juvenile idiopathic arthritis: A single-centre experience.

OBJECTIVES: The purpose of this study is to evaluate the performances of recently proposed Pediatric Rheumatology International Trials Organization criteria versus current International League of Associations for Rheumatology criteria for systemic juvenile idiopathic arthritis (sJIA). METHODS: The study was performed at the Department of Pediatric Rheumatology in Istanbul Faculty of Medicine with a retrospective design, covering the date range 2010-2021. Patients diagnosed with sJIA, Kawasaki disease and common autoinflammatory diseases were included. Both the International League of Associations for Rheumatology and Pediatric Rheumatology International Trials Organization classification criteria were applied to each patient and cross-checked with expert rheumatologist diagnosis. RESULTS: Eighty-two patients with sJIA were compared against 189 (74 Kawasaki disease, 83 familial Mediterranean fever, 16 mevalonate kinase deficiency, 10 cryopyrin-associated periodic syndromes, and 6 tumour necrosis factor receptor-associated periodic syndrome) patients. The Pediatric Rheumatology International Trials Organization criteria demonstrated higher sensitivity (62.2% vs 80.5%, P =.003) but comparable specificity (90.5% vs 91%) as regards the International League of Associations for Rheumatology criteria. CONCLUSIONS: The revised criteria appear to enhance the ability to provide early recognition and pertinent classification of sJIA. No superiority was observed in segregating sJIA from common autoinflammatory diseases and Kawasaki disease, namely in terms of specificity.

An overview of the relationship between juvenile idiopathic arthritis and potential environmental risk factors: Do early childhood habits or habitat play a role in the affair?

AIM: The current study was undertaken to evaluate the influence of breastfeeding on the development and outcome measures of juvenile idiopathic arthritis (JIA). The second aim was to determine the consequences of particular sociodemographic and sociocultural characteristics and nutritional behavior of early childhood on JIA. METHODS: The study includes the patients diagnosed with JIA and regularly followed up at the Department of Pediatric Rheumatology in Istanbul University-Cerrahpasa. The comparison group consisted of healthy subjects and patients with juvenile systemic lupus erythematosus (jSLE). A face-to-face survey method was conducted with the parents of the participants between February 1, 2021, and September 1, 2021. RESULTS: The mean age of the JIA cohort (n = 324) was 12.2 ± 4.7 years, with a female ratio of 64.8%. The breastfeeding rate differed from the control groups (253 healthy subjects and 88 patients with jSLE) but was higher with a value of 94.8%. There was no difference between the groups (P = .097, P = .064) or within the subgroups of JIA (P = .12) regarding breastfeeding duration. Cow's milk introduction time (P = .02, P = .0001), household pet-keeping (P = .001), income level (P = .0001), maternal literacy (P = 0.013) made a statistical difference vs the control groups. CONCLUSION: No relationship was established between the rate or duration of breastfeeding and the development or severity of JIA. The early introduction of cow's milk was found to be higher in the patient cohorts. The income level and maternal literacy appeared to be relevant with the high disability and damage scores, and frequent relapse rates. Secondhand smoking, higher in JIA, may prompt the basis of primary preventable strategies in JIA.

A case of juvenile systemic sclerosis and congenital pulmonary airway malformation related mucinous adenocarcinoma of the lung: paraneoplastic syndrome or just a coincidence?

BACKGROUND: Juvenile systemic sclerosis (JSS) is an extremely rarely seen auto-immune disease characterized by the increased fibrosis of skin and internal organs. Congenital pulmonary airway malformation (CPAM) is a developmental disorder of the lung, characterized by atypical cell hyperplasia which creates the ground for lung adenocarcinoma. In general, CPAM is diagnosed in early childhood, due to recurrent respiratory symptoms including cough, hemoptysis and respiratory infections. Although rare, there are some sporadic asymptomatic cases of CPAM that have been reported. We present a case with a coincidental presence of two rare diseases: JSS and CPAM. CASE: An adolescent female patient was admitted to hospital due to clinical signs of JSS. During the followup, the patient had been diagnosed with cystic adenoid malformation of the lung complicated by mucinous adenocarcinoma. The patient was previously healthy with an unremarkable history, including lack of respiratory symptoms. Left inferior lobectomy was performed. Considering the small size of malignant loci, the total resection of the tumor and absence of any sign for metastasis disease, adjuvant therapy was not scheduled. We haven`t found a pediatric case of CPAM associated adenocarcinoma of the lung presented by signs of JSS in the literature. In this case, the clinical signs of JSS possibly represent part of the paraneoplastic syndrome related to adenocarcinoma of the lung. CONCLUSIONS: Internal organ involvement, including respiratory system, should not be omitted even in asymptomatic patients with JSS. Auto-antibody negativity represents a clue for the possible underlying condition. Further studies with a higher number of patients would reveal more relevant data.

Asymptomatic SARS-CoV-2 seropositivity: patients with childhood-onset rheumatic diseases versus healthy children.

OBJECTIVE: We aimed to find out the asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence among pediatric patients with rheumatic diseases and healthy children and to compare them with each other. METHODS: Patients with familial Mediterranean fever (FMF), juvenile idiopathic arthritis (JIA), and juvenile systemic lupus erythematosus (jSLE) and healthy children as healthy control (HC) group who remained asymptomatic during the pandemic are examined by ELISA immunoglobulin (Ig) A and IgG tests in this cross-sectional study. RESULTS: Overall, 149 subjects (90 females) were included in the study. While IgA was positive in 15 subjects (10%) (HC: 8, jSLE: 3, FMF: 2, JIA: 2; p = 0.196), IgG was positive in 14 subjects (9.4%) (HC: 7, JIA: 5, FMF: 1, jSLE: 1; p = 0.156). Nineteen subjects (12.75%) were IgA or IgG positive (HC: 8, JIA: 5, jSLE: 3, FMF: 3; p = 0.644). Although not significant, seropositivity was more often in HC group. Both IgA and IgG positivity were not found to be related to age, sex, underlying rheumatic diseases, and received treatments of the patients. CONCLUSION: We revealed that patients with childhood-onset rheumatic diseases, even if they receive immunosuppressive medication such as biologic or conventional disease-modifying anti-rheumatic drugs, might have an asymptomatic SARS-CoV-2 infection, similarly to their healthy peers. Key points • Although it has been already known that children are most likely to have asymptomatic SARS-CoV-2 infection, there is a lack of data on the disease course of children with rheumatic disease. • There was no significant difference regarding the asymptomatic SARS-CoV-2 seropositivity rates between healthy children and the patients with childhood-onset rheumatic diseases. • Patients with childhood-onset rheumatic diseases, even if they receive immunosuppressive medication, might have asymptomatic SARS-CoV-2 infection, similarly to their healthy peers.

Systolic and Diastolic Cardiac Functions in Juvenile Spondyloarthropathies.

BACKGROUND/OBJECTIVE: Juvenile spondyloarthropathies (JSpAs) are a group of inflammatory diseases characterized by asymmetric peripheral arthritis (especially in lower extremities), axial skeleton involvement, and enthesitis. Although cardiovascular findings of inflammatory diseases such as juvenile systemic lupus erythematosus (SLE) and juvenile scleroderma (SD) are well documented, there are only a few studies assessing the cardiovascular consequences of JSpA in the literature. METHODS: Forty patients with JSpA and 20 healthy controls were included into this cross-sectional study. Cardiac functions of the participants were evaluated by conventional echocardiography and pulse-wave (PW) tissue Doppler. RESULTS: The patients with JSpA had higher mitral lateral S (p = 0.005) and E' wave (p < 0.001), tricuspid A' wave (p = 0.03), ejection fraction (p = 0.03) and shortening fraction (p = 0.01) than the control patients. In contrast, the patients with JSpA had lower left ventricle MPI (p = 0.01) and the ratio of tricuspid E'/A' waves (p = 0.05). Patients with enthesitis detected on magnetic resonance imaging had lower ejection fraction (p = 0.05), the ratio of E/A waves (p = 0.03) and had higher Mitral lateral A' wave (p = 0.01) than those without. There was a significant inverse correlation between the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and PW transmitral A velocity (r = -0.256, p = 0.03), the BASDAI score and tricuspid annular plane systolic excursion (r = -0.301, p = 0.04), the BASDAI score and the ratio of E/E' waves (r = -0.276, p = 0.02), and the Juvenile Spondyloarthritis Disease Activity Index and PW transmitral A velocity (r = -0.246, p = 0.04). CONCLUSIONS: In this study, we report the possible early signs of RV diastolic dysfunction and possible association between magnetic resonance imaging-confirmed enthesitis and lower LV systolic functions. Early identification of cardiac dysfunctions can help with prevention of long-term cardiovascular complications.

Shear wave elastography evaluation of liver, pancreas, spleen and kidneys in patients with familial mediterranean fever and amyloidosis.

OBJECTIVES: Amyloid deposits in a visceral organ can contribute to tissue stiffness that could be measured with shear wave elastography (SWE). We aimed to investigate changes in organ stiffness in conjunction with laboratory parameters in patients with Familial Mediterranean Fever (FMF) and amyloidosis. METHODS: This prospective study included 27 FMF patients, 11 patients with amyloidosis, and 38 healthy controls. Median shear wave elasticity values of the liver, spleen, both kidneys, and pancreas on SWE were compared among study and control groups. The mean values of CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate) were compared by the t-test and the median of SAA (serum amyloid A protein) was compared with the Mann-Whitney U test between FMF groups with and without amyloidosis. Spearman's correlation analysis was performed to reveal the association between stiffness values and laboratory parameters. RESULTS: The median liver, spleen, kidney, and pancreas elasticity values were significantly higher in the FMF group with amyloidosis compared to control subjects. The median kidney stiffness values in the FMF group with or without amyloidosis were significantly higher compared to control subjects. Median liver stiffness values in FMF patients with amyloidosis were significantly higher than FMF patients without amyloidosis. There were statistically significant positive correlations between the CRP (p = 0.001, r = 0.56), ESR (p = 0.001, r = 0.61), and SAA (p = 0.002, r = 0.53) levels with spleen stiffness, and CRP (p = 0.006, r = 0.48) and ESR (p = 0.001,r = 0.61) levels with pancreas stiffness, and ESR (p = 0.004, r = 0.51) levels with the left kidney stiffness. CONCLUSION: SWE could be a potential tool for noninvasive follow-up of FMF patients and also amyloid deposition. ADVANCES IN KNOWLEDGE: Both acute inflammation and amyloidosis in the FMF patients could increase organ stiffness.

Biologics in juvenile idiopathic arthritis-main advantages and major challenges: A narrative review.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. The disease is divided in different subtypes based on main clinical features and disease course. Emergence of biological agents targeting specific pro-inflammatory cytokines responsible for the disease pathogenesis represents the revolution in the JIA treatment. Discovery and widespread usage of biological agents have led to significant improvement in JIA patients' treatment, with evidently increased functionality and decreased disease sequel. Increased risk of infections remains the main discussion topic for years. Despite the slightly increased frequency of upper respiratory tract infections reported in some studies, the general safety of drugs is acceptable with rare reports of severe adverse effects (SAEs). Tuberculosis (TBC) represents the important threat in regions with increased TBC prevalence. Therefore, routine screening for TBC should not be neglected when prescribing and during the follow-up of biological treatment. Malignancy represents a hypothetical complication that sometimes causes hesitations for physicians and patients in its prescription and usage. On the other hand, current reports from the literature do not support the increased risk for malignancy among JIA patients treated with biological agents. A multidisciplinary approach including a pediatric rheumatologist and an infectious disease specialist is mandatory in the follow- up of JIA patients. Although the efficacy and safety of biological agents have been proven in different studies, there is still a need for long-term, multicentric evaluation providing relevant data.

Pediatric Behçet's Disease.

Behçet's Disease (BD) is a systemic vasculitis firstly described as a disorder causing aphthous lesion in oral and genital mucosae and uveitis. The disease has an extremely unique distribution characterized by the highest incidence in communities living along the historical Silk road. Although our understanding of the etiopathogenesis of BD has expanded over time, there are still lots of unidentified points in the underlying mechanisms of the disease. The accepted opinion in the light of the current knowledge is that various identified and/or unidentified infectious and/or environmental triggers can take a role as a trigger in individuals with genetic susceptibility. Although the disease usually develops in young adulthood, it is reported that about 15-20% of all Behçet's patients develop in childhood. Pediatric BD differs from adult BD not only with the age of onset but also in the frequency and distribution of clinical findings, disease severity and outcome. While gastrointestinal system involvement, neurological findings, arthralgia and positive family history are more common in children, genital lesions and vascular lesions are more common in adult patients. In addition, a better disease outcome with lower severity score and activity index has been reported in children. The diagnosis of the disease is made according to clinical findings. It can be challenging to diagnose the disease due to the absence of a specific diagnostic test, and the long time interval from the first finding of the disease to the full-blown disease phenotype in pediatric cases. Therefore, many classification criteria have been proposed so far. The widely accepted ones are proposed by the International Study Group. The new sets of classification criteria which is the only one for pediatric BD were also developed for pediatric cases by the PEDBD group. The primary goal for the treatment is preventing the organ damages by suppressing the ongoing inflammation and forestalling the disease flares. The treatment of the BD can be onerous due to its multisystemic nature and a multidisciplinary approach is essential for the management of the patients. In this review article, the definition, clinical findings, epidemiology, etiopathogenesis, and treatment will be discussed.

Anti-nuclear antibody testing in children: How much is really necessary?

BACKGROUND: Anti-nuclear antibody (ANA) testing is most commonly ordered by general pediatricians to evaluate children with musculoskeletal system complaints. Given the limited utility of the test, we aimed to estimate the effectiveness of ordering ANA testing in childhood. METHODS: Children referred to our department to be examined due to positive ANA findings between 2008 and 2020 were included in the study. Those with less than one-year follow-up period, those with previously known rheumatic or autoimmune disease, and those diagnosed as an autoimmune and/or rheumatic disease at the first visit were excluded. Data were obtained from their medical records, retrospectively. The parents of all of the patients were called via phone, data were verified, and missing information was collected. RESULTS: Three hundred and fifty-eight patients (230 females) were eligible for the study. The median age of positive ANA findings was 9.31 (1.3-17.86) years and the median follow-up duration was 4.85 (1-11.91) years. Most of the patients had no underlying disease (n = 337, 94.1%). The most common reason for ordering ANA testing was to evaluate musculoskeletal system symptoms (n = 225, 62.8%). None of our patients referred to us due to positive ANA findings developed any autoimmune conditions or ANA associated rheumatic disease. Hypermobility syndrome is the most common final diagnosis among our ANA-positive patients. CONCLUSION: We suggest that instead of using it as a screening tool, ANA testing should be performed only if there is a strong suspicion of autoimmune diseases or certain rheumatic conditions, such as systemic lupus erythematosus.

The role of Mediterranean fever gene variants in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.

This study was conducted to investigate the relationship between clinic features and Mediterranean fever gene (MEFV) variants in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. In total, 167 patients with PFAPA syndrome were included in the study. Female:male ratio of the patients was 0.75 (72 females, 95 males). In total 59.9% of patients with PFAPA had at least one MEFV variant and the most common heterozygous variants were M694V in 29.3% of the patients (40/167), E148Q in 8.3% (14/167), and V726A in 7.1% (12/167). The median age at the disease onset was significantly higher and the median duration of the episodes was significantly lower in patient with variants in exon 10 comparing to the others (both p = 0.01). Similarly, the median age at the disease onset was significantly higher (p = 0.01) and the median duration of the episodes was significantly lower (p = 0.04) in patient with MEFV variants than in the remaining patients. There were no significant differences according to the genotypes of the patients in terms of both treatment response and the frequency of clinical findings.Conclusion: In PFAPA syndrome, MEFV variants may be a modifier for disease onset and attack duration. What is Known: • Due to periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome having clinical findings resembling familial Mediterranean fever (FMF), it can be difficult to distinguish PFAPA syndrome and FMF especially in endemic regions for FMF. • Underlying MEFV mutations could affect the periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome's clinical presentation and response to treatment. What is New: • Having one of the underlying MEFV variants is related to later disease onset and shorter episode duration in patients with PFAPA syndrome.

Tocilizumab therapy in juvenile systemic sclerosis: a retrospective single centre pilot study.

To evaluate the efficacy and safety of anti-interleukin (IL)-6 receptor antibody tocilizumab (TCZ) as a treatment option of juvenile systemic sclerosis (JSS). Nine JSS patients were assigned to a TCZ, additionally to conventional treatment (steroids, methotrexate, mycophenolate-mofetil). The modified Rodnan skin score (mRSS), carbon-monoxide diffusion capacity (DLCO), thorax high-resolution tomography (HRCT), patient global assessment (PGA) and Juvenile Systemic Sclerosis Severity (J4S) score were used to explore the efficacy of treatment. Nine JSS patients were treated with TCZ with a median treatment duration of 10 (1-21) months. Nine patients (77.8%) had radiologically confirmed improvement on thorax HRCT, 7 (77.8%) had decreased PGA (mean pre-treatment PGA 3.7 vs. 2.3 post-treatment PGA 2), 6 (66.7%) had increased DLCO (mean pre-treatment DLCO 69.14% vs. post-treatment DLCO 79.50%) after the TCZ treatment. In all patients mRSS and the J4S decreased: 26.1 vs. 19.7 and 8.2 vs. 4.7, respectively. Changes in mRSS, DLCO, PGA and J4S were statistically significant: p = 0.012, 0.04, 0.026 and 0.007, respectively. All patients tolerated well TCZ treatment. JSS is a rare condition characterized with skin fibrosis and internal organ involvement. Tocilizumab represents a potential treatment option for patients unresponsive to conventional treatment. Long-term prospective studies with higher number of patients are needed to provide more relevant data.

Independent risk factors for resolution of periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome within 4 years after the disease onset.

BACKGROUND/OBJECTIVE: Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a polygenic disease with unknown etiology. In this retrospective cohort study, we aimed to evaluate the risk factors for the resolution of PFAPA syndrome within 4 years after the onset. METHODS: In total, 466 patients with PFAPA syndrome that are being followed up our department were included into the study. Between May 2020 and September 2020, medical charts of the patients were reviewed retrospectively. RESULTS: The median age of the patients at the time of the study and at disease onset were 8.6 (2.9-20.5; IQR 6.9-10.6) years and 18 (1-84; IQR 11-31) months. On univariate analysis age at disease onset (p = 0.003), positive family history of PFAPA syndrome (p = 0.04), absence of myalgia (p = 0.04), and absence of headache (p = 0.003) were all associated with the resolution of PFAPA syndrome within 4 years after the onset. Multivariate logistic regression analysis revealed that age at disease onset (OR 1.04, 95% CI 1.01-1.07, p = 0.002), positive family history of PFAPA syndrome (OR 2.69, 95% CI 1.12-6.48, p = 0.02), and absence of headache (OR 0.2, 95% CI 0.05-0.74, p = 0.01) were independent risk factors for the resolution of PFAPA syndrome within 4 years after the onset. CONCLUSION: We report later age of disease onset, positive family history of PFAPA syndrome, and absence of headache as independent risk factors for resolution of PFAPA syndrome within 4 years after the onset. KEY POINTS: • Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a multifactorial disease with unknown etiology. • Although, PFAPA syndrome usually resolves within 3-5 years after the disease onset, it can persist for years and even continue into adulthood. With our current knowledge, there is no clue to predict which patients will have a long disease course and which patients will not. • Later age of disease onset, positive family history of PFAPA syndrome and absence of headache as independent risk factors for resolution of PFAPA syndrome within 4 years after the onset.

Does immunosuppressive treatment entail an additional risk for children with rheumatic diseases? A survey-based study in the era of COVID-19.

The aim of the research was to further extend current knowledge of whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease 2019 (COVID-19) entails a risk for children with various rheumatic diseases under immunosuppressive treatment. Telephone survey was administered by conducting interviews with the parents from May 1, 2020 to May 20, 2020. A message containing a link to the actual questionnaire was sent to their phones simultaneously. The medical records of the patients were reviewed for gathering information about demographic data, clinical follow-up, and treatments. Patients who were followed-up under immunosuppressive treatment (n = 439) were attempted to be contacted. The diagnostic distribution of patients (n = 414) eligible for the study was as follows: juvenile idiopathic arthritis (JIA) (n = 243, 58.7%), autoinflammatory diseases (n = 109, 26.3%), connective tissue diseases (n = 51, 12.3%), and vasculitis (n = 11, 2.7%). In the entire cohort, the mean age was 12 ± 4.7 years, and 54.1% (n = 224) were female. Nine patients have attended the hospital for COVID-19 evaluation, 6 of whom were in close contact with confirmed cases. One patient with seronegative polyarticular JIA, previously prescribed methotrexate and receiving leflunomide during pandemic was identified to be diagnosed with COVID-19. None, including the confirmed case, had any severe symptoms. More than half of the patients with household exposure did not require hospitalization as they were asymptomatic. Although circumstances such as compliance in social distancing policy, transmission patterns, attitude following contact may have influenced the results, immunosuppressive treatment does not seem to pose an additional risk in terms of COVID-19.