Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis on anti-interleukin-1 or -6 therapy.

OBJECTIVES: The aim of this study is to investigate the effect of anti-interleukin (IL)-1/-6 biologics on systemic juvenile idiopathic arthritis (sJIA)-associated macrophage activation syndrome (MAS). METHODS: Demographic, clinical, and laboratory data of patients followed up with a diagnosis of sJIA-associated MAS assessed from sixteen pediatric rheumatology centers across the country. The clinical and laboratory features of MAS developing while on biological drugs were compared with those without this treatment. RESULTS: One hundred and sixty-two patients were included in the study. 45 of the MAS events were detected under the effect of anti-IL-1/-6 biologics, while the patients experiencing the remaining 155 events have not received biological treatment in the last three months. Platelet count [128 (72-232) vs 199 (130-371) 109/l], ferritin level on admission [1107 (676-2050) vs 2863 (1193-9562) ng/ml], C-reactive protein level [15.4 (2.9-56) vs 90 (32-160) mg/l], erythrocyte sedimentation rate [13 (3-36) vs 43.5 (13-77) mm/h] and fever duration [5 (4-7.5) vs 10 (7-14.3) days] were found lower in the group under the impact of anti-IL-1/-6 biologics. Among patients treated with biologics, 26.6% did not meet the published 2016 MAS classification criteria at presentation. The rates of hepatomegaly and splenomegaly were relatively lower in the canakinumab-treated group when compared with those receiving other biologicals or to patients, not on biologicals. CONCLUSION: Anti-IL-1/-6 therapies can mask the clinical and laboratory features of MAS, and proposed guidelines for MAS classification criteria may not be met.

Evaluation of pediatric rheumatologists' approach to rituximab use: a questionnaire study.

Rituximab (RTX) is a chimeric monoclonal antibody that targets the CD20 antigen on B cells and is used in various autoimmune disorders. In this study, we aimed to measure the awareness of pediatric rheumatologists about the use of RTX through a survey. Between February and March 2023, a 42-question survey was sent via email to pediatric rheumatology specialists in Turkey. The participants were questioned for which diagnoses and system involvement they preferred to use RTX, which routine tests they performed, vaccination policy, and adverse events that occurred during or after infusion. Forty-one pediatric rheumatologists answered the survey. They prescribed RTX most frequently for systemic lupus erythematosus (87.8%) and ANCA-associated vasculitis (9.8%). Prior to the administration of RTX, 95% of clinicians checked renal and liver function tests, as well as immunoglobulin levels. The most frequently tested hepatitis markers before treatment were HBsAg and anti-HBs antibody (97.6%), while 85.4% of rheumatologists checked for anti-HCV. Clinicians (31.4%) reported that they postpone RTX infusion 2 weeks following an inactivated vaccine. Sixty-one percent of rheumatologists reported starting RTX treatment 1 month after live vaccines, while 26.8% waited 6 months. The most frequent adverse events were an allergic reaction during RTX infusion (65.9%), hypogammaglobulinemia (46.3%), and rash (36.6%). In the event of hypogammaglobulinemia after RTX treatment, physicians reported that they frequently (58.5%) continued RTX after intravenous immunoglobulin administration. CONCLUSIONS: RTX has become a common treatment option in pediatric rheumatology in recent years. Treatment management may vary between clinician such as vaccination and routine tests. WHAT IS KNOWN: • During the course of rituximab therapy, clinicians should be attentive to specific considerations in pre-treatment, during administration, and in post-treatment patient monitoring. WHAT IS NEW: • There are differences in practice among clinicians in the management of RTX therapy. These practice disparities have the potential to impact the optimal course of treatment. • This study highlights that standardized guidelines are needed for RTX treatment in pediatric rheumatology, particularly for vaccination policies and routine tests.

Do the features of juvenile psoriatic arthritis change according to age? A comprehensive evaluation of the PeRA Research Group Registry.

OBJECTIVES: To describe the clinical features and treatment outcomes of children with juvenile psoriatic arthritis (JPsA) and to compare the distinct patterns of the disease between early-onset and late-onset age groups. METHODS: Patients with JPsA followed regularly for at least 6 months between 2010-2020 in 7 pediatric rheumatology centers in Turkey were included in the study. The demographic features, clinical manifestations, treatment strategies, and outcomes of the patients were evaluated retrospectively. RESULTS: Eighty-seven (46 male/41 female) patients were included in the study. The mean age at diagnosis was 11.9 ± 4.5. Fifty-seven (65.5%) patients had psoriasis at the time of diagnosis, arthritis preceded psoriasis in 10 (11.5%) patients. Thirty (34.5%) patients had dactylitis, 28 (32.2%) had nail pitting, 36 (41.4%) had involvement of the small joints, 20 (23%) had enthesitis. Sacroiliitis was detected in 11 (12.6%) patients by magnetic resonance imaging. Anti-nuclear antibodies (ANA) were positive in 35 (40.2%) patients. Twelve children (%13.8) were in the early-onset (<5 years) group. Uveitis and ANA positivity were more common in the early-onset group. Active joint counts and activity scores of our patients showed significant improvement at 6th month and at the last control compared with baseline. CONCLUSION: About one-third of patients with JPsA do not have psoriasis at the time of diagnosis. In some patients, no skin lesion is seen during the course of the disease. Children with psoriatic arthritis seem to display two different phenotypes. Younger children have female predominance, ANA positivity, and uveitis, while older children have more axial involvement.

Not easy-peasy to diagnose: familial Mediterranean fever unaccompanied by fever.

Classical attacks of familial Mediterranean fever (FMF) are often accompanied by fever, but some of the patients have attacks without fever. This study aimed to compare the characteristics of FMF patients with and without fever during their attacks and draw attention to the different clinical presentations of FMF in children. Medical files of patients aged 0-18 years who were followed up with the diagnosis of FMF in two reference pediatric rheumatology centers were reviewed retrospectively. The patients were divided into two groups: children who had had no fever in any of their attacks were assigned as group 1, and those who had fever during their attacks were classified as group 2. Out of 2003 patients evaluated, 191 (9.53%) patients had attacks not accompanied by fever and their median age at onset of symptoms (7.0 vs. 4.0 years, p < 0.001) and the median age at diagnosis (8.6 vs. 6.0 years, p < 0.001) were significantly higher; however, group 2 had a delay in diagnosis. The annual number of attacks and abdominal attacks were more common in group 2; arthritis, arthralgia, erysipelas-like rash, exercise-induced leg pain, and myalgia were more common in group 1.    Conclusion: The data from the assessment of children with FMF attacks not accompanied with fever were presented for the first time. Children with late age onset of FMF and dominance of musculoskeletal features may display attacks not accompanied with fever. What is Known: • Familial Mediterranean fever (FMF) is the most common inherited auto-inflammatory disease, characterized by recurrent attacks of fever, serositis, and musculoskeletal symptoms. • Although fever is the most common symptom, few studies have reported attacks without fever. What is New: • The aim of this study was to identify patients with FMF but without fever during attacks and to demonstrate their distinctive presentations. • We found that 7% of our patients had afebrile attacks with predominant musculoskeletal symptoms and were diagnosed earlier than patients with febrile attacks, probably due to early referral to pediatric rheumatology clinics.

PREDICT-crFMF score: A novel model for predicting colchicine resistance in children with familial Mediterranean fever.

OBJECTIVES: To develop a novel scoring system to predict colchicine resistance in Familial Mediterranean fever (FMF) based on the initial features of the patients. METHODS: The medical records of patients were analyzed prior to the initiation of colchicine. After generating a predictive score in the initial cohort, it was applied to an independent cohort for external validation of effectiveness and reliability. RESULTS: Among 1418 patients with FMF, 56 (3.9%) were colchicine resistant (cr) and 1312 (96.1%) were colchicine responsive. Recurrent arthritis (4 points), protracted febrile myalgia (8 points), erysipelas-like erythema (2 points), exertional leg pain (2 points), and carrying M694V homozygous mutation (4 points) were determined as the parameters for predicting cr-FMF in the logistic regression model. The cut-off value of 9 was 87% sensitive and 82% specific to foresee the risk of cr-FMF in the receiver operating characteristic. Validation of the scoring system with an independent group (cr-FMF = 107, colchicine responsive = 1935) revealed that the cut-off value was 82% sensitive and 79% specific to identify the risk of cr-FMF. CONCLUSIONS: By constructing this reliable and predictor tool, we enunciate that predicting cr-FMF at the initiation of the disease and interfering timely before the emergence of complications will be possible.

Approach to switching biologics in juvenile idiopathic arthritis: a real-life experience.

The primary aim of the treatment of juvenile idiopathic arthritis (JIA) is complete remission and minimizing the development of complications. Though biologic agents (BAs) provide better disease control, data related to BA switching patterns in JIA patients are scarce. This study aimed to determine the BA switching patterns in JIA patients. The study included children with JIA that received ≥ 1 BAs. Disease activity was evaluated based on the juvenile arthritis disease activity score 71 (JADAS71). Demographic data, clinical and laboratory findings, BA switching patterns, and the rationales for BA switching were recorded. The study included 177 (82 female and 95 male) JIA patients that received ≥ 1 BAs. Mean age at diagnosis of JIA was 9.1 ± 4.9 years. BAs were prescribed a median of 14 months (range: 3-66 months) after diagnosis. Among the 177 patients, 31 (17.5%) required BA switching a median 10.5 months (range: 3-38 months) after initiation of the first BA. Among all the BAs that were switched to after administration of the first BA, tocilizumab was the most commonly switched (n = 15). The most common reason for BA switching was inadequate response (n = 29). BAs were switched 2 times in 5 patients and 3 times in 1 patient. When patients that switched BAs 1 time were compared to those that switched 2 and 3 times there were not any differences in terms of JIA types, whereas those that switched 2 and 3 times had a higher active joint count and JADAS71 score after 6 months of initiation of the first BA. As some of the JIA patients could not achieve remission despite using the prescribed BA, BA switching was required. Herein, we provide data on both BA switching patterns and requirements, which may improve the management of JIA patients.

Hepatitis B vaccination response of treatment-naive patients with juvenile idiopathic arthritis.

To evaluate the vaccine response of treatment-naive juvenile idiopathic arthritis (JIA) patients who were fully vaccinated against Hepatitis B Virus (HBV) and then compare their antibody status with healthy controls. In this multicenter study, initial visit hepatitis B surface antigen (HbsAg) and anti-hepatitis B surface antibody (anti-Hbs) titers of 262 treatment-naive JIA patients who were followed up regularly between May 2015 and October 2019 were evaluated retrospectively from patients' medical records and compared with 276 healthy peers. Both HbsAg and anti-Hbs antibody titers were tested by the ELISA technique. Anti-HBs titers ≥ 10 IU/L were considered as reactive indicating seroprotection against HBV. In the JIA group, seropositivity rate was 59.1% while 72.9% of the control group were immune against HBV (p = 0.002). The median titer for anti-Hbs was 14 (range: 0-1000) IU/L in the patient group and 43.3 (range: 0-1000) IU/L in the control group (p = 0.01). Neither JIA patients nor healthy controls were positive for HbsAg. Patients with JIA vaccinated according to the national vaccination schedule were evaluated at their first visit in pediatric rheumatology outpatient clinics for anti-Hbs presence and it was found that they have lesser seroprotectivity than their age and sex-matched routinely vaccinated, healthy peers. So, to complete missing vaccines and booster vaccine doses, assessing the immune status of the patients at the time of diagnosis against HBV should be in the check-list of physicians dealing with pediatric rheumatic diseases.

Adherence to best practice consensus guidelines for familial Mediterranean fever: a modified Delphi study among paediatric rheumatologists in Turkey.

BACKGROUND: Although not validated fully, recommendations are present for diagnosis, screening and treatment modalities of patients with familial Mediterranean fever (FMF). OBJECTIVE: To review the current practices of clinicians regarding FMF and reveal their adherence to consensus guidelines. METHODS: Fifteen key points selected regarding the diagnosis and management of FMF were assessed by 14 paediatric rheumatologists with a three-round modified Delphi panel. RESULTS: Consensus was reached on the following aspects: genetic analysis should be ordered to all patients when clinical findings support FMF, but its result is not decisive alone. In the absence of clinical features, colchicine should be commenced when two pathogenic alleles and family history of amyloidosis are present. Serum amyloid A testing at each visit is recommended in patients resistant to colchicine, with subclinical inflammation and family history of amyloidosis. Consensus was reached on both the definition of colchicine resistance and starting biologic in resistant cases. Cost, efficiency, ease of use, treatment adherence, accessibility and emergence of adverse events are the factors affecting the choice of biologic agents. In patients without any attack and evidence of subclinical inflammation within the last 6 months following initiation of biologics, treatment dose intervals can be prolonged. CONCLUSION: A consensus was achieved regarding the routine diagnosis and screening and treatment of FMF patients. The definition of colchicine resistance was made and a protocol was created for prolongation of treatment intervals of biologic agents. We anticipate that the results of the study reveal real-life data on the approach to patients in clinical practice.

Differences and similarities of multisystem inflammatory syndrome in children, Kawasaki disease and macrophage activating syndrome due to systemic juvenile idiopathic arthritis: a comparative study.

To compare the clinical and laboratory findings of multisystem inflammatory syndrome in children (MIS-C), patients with Kawasaki disease (KD) and with macrophage activating syndrome due to systemic juvenile idiopathic arthritis (sJIA-MAS) on real-life data. Patients diagnosed with MIS-C, KD, and sJIA-MAS from 12 different centers in Turkey who were followed for at least 6 months were included in the study. Demographic, clinical, and laboratory findings of all patients were analyzed. A total of 154 MIS-C, 59 KD, and 31 sJIA-MAS patients were included. The median age of patients with MIS-C were higher than those with KD while lower than those with sJIA-MAS (8.2, 3, 12 years, respectively). Myalgia (39.6%), cardiac (50.6%), gastrointestinal (72.7%), and neurological (22.1%) involvements were more common in patients with MIS-C compared to others. MIS-C patients had lower levels of lymphocyte (950 vs 1700 cells/µl) and thrombocyte (173,000 vs 355,000 cells/µl) counts and higher pro-BNP (1108 vs 55 pg/ml) levels than KD. Ferritin levels were higher in patients with MIS-C compared to patients with KD while they were lower than patients with sJIA-MAS (440, 170, 10,442 ng/ml, respectively). Patients with MIS-C had a shorter duration of hospitalization than sJIA-MAS (p = 0.02) while they required intensive care unit admission more frequently (55 vs 8 patients, p < 0.001). The median MAS/sJIA score of MIS-C patients was - 1.64 (- 5.23 to 9.68) and the median MAS/sJIA score of sJIA-MAS patients was -2.81 ([- 3.79] to [- 1.27]). MIS-C patients displayed certain differences in clinical and laboratory features when compared to KD and sJIA-MAS. Definition of the differences and similarities between MIS-C and the other intense inflammatory syndromes of childhood such as KD and MAS will help the clinicians while making timely diagnosis.

Low disease activity state in juvenile-onset systemic lupus erythematosus.

OBJECTIVES: To determine the rate of achieving The Lupus Low Disease Activity State (LLDAS) in children with systemic lupus erythematosus (SLE) for tracing pertinent treatment modalities. METHODS: A total of 122 juvenile-onset SLE (jSLE) patients from six pediatric rheumatology centers in Turkey were enrolled in the study. LLDAS-50 was defined as encountering LLDAS for at least 50% of the observation time. According to the achievement of LLDAS-50, clinical features, immunological profiles, and treatments of patients with jSLE have been revealed. RESULTS: LLDAS of any duration was achieved by 82% of the cohort. Although only 10.8% of the patients achieved remission, 68.9% reached LLDAS-50. A significant difference was found between patients who reached LLDAS-50 and those who did not, in terms of the time to reach low-dose corticosteroid treatment (p = 0.002), the presence of subacute cutaneous findings (p = 0.007), and the presence of proteinuria (p = 0.002). Both of the groups were under similar treatment approaches. However, the number of patients being treated with corticosteroids at the last visit was found to be significantly higher in patients who achieved LLDAS-50 (p<0.001). CONCLUSION: Targeting LLDAS in jSLE, even with long-term, low-dose corticosteroid use, seems to be an achievable goal in clinical practice.

Hematological involvement in pediatric systemic lupus erythematosus: A multi-center study.

Introduction: Systemic lupus erythematosus (SLE) may present with features of several systems, including hematological manifestations. In this study, we aimed to evaluate the characteristics of hematological involvement and assess possible associations and correlations in pediatric SLE patients. Method: This is a retrospective multi-center study. The medical records of pediatric SLE patients followed between January 2000 and June 2020 were analyzed. All children fulfilled the criteria of the Systemic Lupus International Collaborating Clinics. Results: The study included 215 children with SLE, 118 of whom had hematological manifestations. Concomitant renal involvement and low C3 levels were significantly more frequent in patients with hematological involvement (p = 0.04, p = 0.008, respectively). Also, anti-cardiolipin, anti-beta-2-glycoprotein I (anti-ß2 GP1), and anti-Sm antibody positivity, and the presence of lupus anticoagulant were more common in the group with hematological findings (p = 0.001 for anti-cardiolipin antibody positivity and p < 0.001 for the positivity of anti-ß2 GP1 antibody, anti-Sm antibody, and lupus anticoagulant). The most common hematologic abnormality was anemia (n = 88, 74.5%), with autoimmune hemolytic anemia constituting the majority (n = 40). Corticosteroids followed by IVIG were the mainstay of treatment. In patients resistant to corticosteroid and IVIG treatments, the most preferred drug was rituximab. Low levels of C3, high SLEDAI score, high incidence of renal involvement, and positive antiphospholipid antibodies were associated with hematological involvement in the univariate analysis. The presence of antiphospholipid antibodies and high SLEDAI score were independently associated with hematological involvement in multivariate analysis (OR: 4.021; 95% CI: 2.041-7.921; p < 0.001 and OR: 1.136; 95% CI: 1.065-1.212; p < 0.001). Conclusion: Hematological abnormalities are frequently encountered in pediatric SLE. Positive antiphospholipid antibodies and high SLEDAI scores were associated with hematological involvement.

The influence of carrying MEFV gene variants on juvenile systemic lupus erythematosus.

Juvenile-onset systemic lupus erythematosus (jSLE) patients typically have a more severe disease course than adults with SLE. We aimed to assess the prevalence and disease course of jSLE patients carrying MEFV variants. MEFV variant analyses were performed in 44 jSLE patients and effect of these variants on disease severity and course was analyzed by SLEDAI score and SLICC/ACR index. Ten of the patients (22.7%) had a MEFV variant. The median (min-max) SLEDAI score and SLICC/ACR index were 2(0-13) and 0(0-3), respectively. Median age at disease onset, disease duration, SLICC/ACR indexes, SLEDAI scores, clinical and laboratory findings of the patients were comparable in carriers of variants and non-carriers. Nineteen patients (43.2%) had biopsy-proven lupus nephritis and four of these patients had MEFV variants. There was no significant difference between patients with and without MEFV carriers in terms of lupus nephritis. Even though not significant statistically, renal involvement was milder in MEFV carriers than non-carriers. The presence of MEFV variants does not increase the overall susceptibility to jSLE in our cohort, while larger number of patients is required to display the protective role of MEFV variants in jSLE.

Comorbidities and phenotype-genotype correlation in children with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease manifesting with phenotypic heterogeneity. The phenotype-genotype correlation is not established clearly yet. Furthermore, some comorbidities such as vasculitis and inflammatory arthritis may accompany FMF. Herein, we aimed to define phenotype-genotype correlation and comorbid diseases of children with FMF. The medical records of 1687 children diagnosed and followed up as FMF were reviewed retrospectively. Disease severity was assessed by PRAS score. A total of 1687 children (841 girls, 846 boys) were involved in the study. The mean ± standard deviation of current age, age at symptom onset, and age at diagnosis were 13.1 ± 5.4, 5.4 ± 4, and 8 ± 4.2 years, respectively. Median (min-max) follow-up period was 3 (0.5-18) years. Among them, 118 (7%) patients had at least one concomitant disease and 72% of them were carrying at least one M694V mutation. Patients with a concomitant disease expressed a more severe course of disease when compared to ones without a concomitant disease (23.7% vs 8.8%, p < 0.001). Children carrying homozygous M694V mutation had significantly earlier age of disease onset and severe disease course (p < 0.001). Forty-four patients (2.6%) were colchicine resistant and most of them were carrying homozygous M694V mutation. Sixteen colchicine-resistant patients were treated with anakinra while 28 received canakinumab. Juvenile idiopathic arthritis (JIA) and immunoglobulin A vasculitis were the most commonly seen associated diseases and the patients with a concomitant disease demonstrated more severe course. This is the largest pediatric cohort studied and presented since now. We confirmed that carrying M694V mutation is associated both with a severe disease course and a predisposition to comorbidities.

Comparison of Pediatric Familial Mediterranean Fever Patients Carrying Only E148Q Variant With the Ones Carrying Homozygous Pathogenic Mutations.

OBJECTIVE: The aims of this study were to compare demographic data, clinical features, and severity scores of familial Mediterranean fever patients carrying E148Q variant with the patients having homozygous pathogenic MEFV mutations and to evaluate both of these groups for the performance of Tel-Hashomer, Livneh, and pediatric diagnostic criteria. METHODS: The demographic and clinical data of patients with familial Mediterranean fever either heterozygous or homozygous for E148Q variant (group 1) and patients with homozygous mutations (M694V, M694I, M680I, V726A) (group 2) were collected retrospectively. All patients were evaluated for 3 diagnostic criteria. RESULTS: E148Q variant was present in 128 patients (22.9%), 112 of whom had heterozygous and 16 of whom had homozygous E148Q mutation. Group 2 had 430 patients (77.1%), 372 of whom had homozygous M694V mutation, 50 of whom had homozygous M680I mutation, 5 of whom had homozygous V726A mutation, and 3 of whom had homozygous M694I mutation. Pleuritis, arthritis, recurrent fever, erysipelas-like erythema, and anemia were significantly more common in group 2 than group 1 (p < 0.05). Moderate and severe Pras scores were significantly higher in group 2 (p < 0.001). During attack-free periods, C-reactive protein, erythrocyte sedimentation rate, and serum amyloid A were found significantly higher in group 2 than in group 1 (p < 0.05). The percentage of children diagnosed according to Tel-Hashomer and pediatric criteria was significantly higher in group 2 than in group 1 (p < 0.05). Both groups show similar diagnostic utility by Livneh criteria. CONCLUSIONS: Children with the E148Q variant met the 3 diagnostic criteria; they had a milder disease course both clinically and in laboratory means.

The Value of Serum Amyloid A Levels in Familial Mediterranean Fever to Identify Occult Inflammation During Asymptomatic Periods.

OBJECTIVE: The aim of this observational study was to evaluate whether there was any correlation between the acute phase reactants in children with familial Mediterranean fever (FMF) during attack and attack-free periods. METHODS: The study was conducted between June 2016 and January 2018. Clinical features and laboratory parameters of children with FMF during attack and attack-free periods were recorded longitudinally. RESULTS: The cohort consisted of 168 children with FMF (84 boys, 84 girls). Median values of acute phase reactants during FMF attacks were 433.5 mg/L (34.0-1780.0 mg/L) for serum amyloid A (SAA), 56.7 mg/L (7.6-379.0 mg/L) for C-reactive protein (CRP), and 37.5 mm/h (5-100 mm/h) for erythrocyte sedimentation rate (ESR). Median values for the same tests in attack-free periods were 3.2 mg/L (0.1-25.0 mg/L), 1.7 mg/L (0.1-12.7 mg/L), and 8 mm/h (1-30 mm/h), respectively. Correlation analyses showed that SAA and CRP were highly correlated in FMF attack (r = 0.67, p < 0.01), but no correlation was found between SAA and ESR levels. C-reactive protein was elevated in 13.6%, ESR in 20.8%, and SAA in 28.5% of the patients during attack-free period. Age at onset, sex of the patients, and characteristics of attacks were found to be not associated with elevated SAA in attack-free period. On the other hand, having homozygous exon 10 mutation and having elevated CRP were found to be associated with high SAA in attack-free period. CONCLUSIONS: C-reactive protein and SAA correlate well with FMF attacks. Therefore, checking for SAA during a FMF attack is not required. However, SAA seems to be the most sensitive method for demonstrating subclinical inflammation in attack-free period. Thus, checking SAA levels might be a valuable tool in selected FMF patients.

Age of onset as an influencing factor for disease severity in children with familial Mediterranean fever.

OBJECTIVES: To define the demographic, clinical and genetic features of familial Mediterranean fever (FMF) patients with early disease onset and to compare them with late-onset FMF patients. METHODS: Patients were divided into two groups according to the age of disease onset: group 1 includes the patients who had their first attack ≤3 years of age; group 2 consisted of patients who had their first attack >3 years of age. Furthermore, we compared the proportion of patients fulfilling the three diagnostic criteria among two groups. RESULTS: Of 1687 patients, 761 had first FMF attack at ≤3 years of age while 926 patients presented with their first manifestation of FMF at >3 years. Delay in diagnosis, fever and peritonitis were significantly higher in group 1. Frequency of arthritis, erysipelas-like erythema, non-nephrotic proteinuria, incomplete attacks, chronic arthritis, arthralgia and mean colchicine dose were significantly higher in group 2. Mean Pras score was higher and the presence of M694V mutation was more frequent in group 1. The percentage of children diagnosed according to Tel-Hashomer and pediatric criteria was significantly higher in group 1 than group 2. However, both groups meet Livneh criteria similarly. CONCLUSION: Although patients with early disease onset seem to have more severe disease course, they are more likely to have a delay in diagnosis. To avoid the diagnostic delay, clinicians should be aware of the findings of FMF in early age.

ADA2 Deficiency: Case Series of Five Patients with Varying Phenotypes.

OBJECTIVE: To describe the clinical features, genotype, and treatment approaches of patients with confirmed adenosine deaminase 2 (ADA2) deficiency with dissimilar phenotypes. METHODS: A case series of five DADA2 patients from three families was presented. The clinical and laboratory data, treatment protocols, and outcome of the patients were recorded from the patients' medical charts. ADA2 gene was screened by next generation sequencing first and then verified by Sanger sequencing. Serum ADA2 enzyme activity was measured by modified spectrophotometric method. RESULTS: The median (min-max) age at onset of symptoms and age at diagnosis were 11 (9-13.8) years and 15 (9-19) years, respectively. The median (min-max) follow-up period was 8 (6-45) months. There was consanguinity in two families (2/3). The main clinical manifestations are musculoskeletal (5/5), dermatological (4/5), and neurological (2/5). Homozygosity for the p.G47R mutation in ADA2 gene was detected in three patients. A homozygous mutation in ADA2 gene (c.650 T > A; p.Val217Asp) was detected in two siblings. Plasma ADA2 enzymatic activity was absent in all patients. Anti-tumor necrosis factor (TNF) therapy was commenced, and all patients became clinically inactive with normal acute-phase reactants. CONCLUSION: ADA2 mutations should be checked in patients with presence of inflammation and livedoid vasculitis when they have neurological findings, especially in the form of stroke; and a history suggesting for an inherited disease; or presence of resistance to conventional treatment. Besides, anti-TNF seems to be useful for treatment of DADA2.

Patient satisfaction and clinical effectiveness of switching from intravenous tocilizumab to subcutaneous tocilizumab in patients with juvenile idiopathic arthritis: an observational study.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of idiopathic inflammatory arthritis affecting children younger than 16 years of age. Tocilizumab (TCZ) is a humanized anti-interleukin 6 (IL-6) receptor antibody that was approved for systemic and polyarticular JIA patients. However, the studies regarding patients' satisfaction while receiving TCZ therapy is scarce. Herein, we aimed to evaluate the effect of subcutaneous (SC) TCZ administration on patient satisfaction and disease control of JIA patients. METHODS: All JIA patients receiving TCZ were included in the study. Clinical features, laboratory findings and JADAS71 scores were recorded at baseline and every 3 months during follow-up. Nine of the patients on intravenous (IV) TCZ treatment were switched to SC form. All patients receiving TCZ-SC were questioned by a clinical nurse specialist (CNS) to assess patient satisfaction. RESULTS: A total of 39 patients receiving TCZ were included in the study. Among them, treatment of nine patients (five female, four male) was switched to SC form with a median of 11.5 (8-69) months after initiation of TCZ. Patients were stable both clinically and in laboratory means at the 3rd month of TCZ-SC treatment. There was no deterioration in terms of active joint counts, physician's VAS, patient's VAS and JADAS71. According to patient satisfaction questionnaire, eight of the patients felt satisfied with SC administrations in terms of life quality, school success and reduced school absenteeism. However, one patient did not agree that the SC form is as effective as IV form and wanted to continue with IV form. CONCLUSION: TCZ is an effective treatment option in JIA and switching from IV to SC route when necessary is found to be an effective and acceptable alternative by the patients as well.

Profile of new referrals to a single pediatric rheumatology center in Turkey.

To describe the demographic characteristics and clinical features of patients referred to a pediatric rheumatology outpatient clinic in Turkey and to compare the final diagnoses with the previous literature data. All new patients referred to pediatric rheumatology outpatient clinic of Kanuni Sultan Süleyman Research and Training Hospital between March 2018 and March 2019 were enrolled to the study. Demographic data, referral patterns, disease related features, physical examination findings and final diagnoses of new referrals were collected prospectively. A total of 2982 new referrals were evaluated in 1-year period. Among them 1561 (52%) had a diagnosis of a rheumatic disease. The frequencies of most common rheumatic diseases were; periodic fever syndromes (47.3%), juvenile idiopathic arthritis (18%) and vasculitis (14.4%), respectively. Non-rheumatic conditions were diagnosed in 1243 patients, among them orthopedic/mechanic problems (27.4%) were the most frequent ones followed by vitamin D deficiency (17.5%) and dermatological problems (9.8%). Patients with non-rheumatic conditions comprised a large part of the pediatric rheumatology outpatient clinic. National registries are required to establish the frequencies of pediatric rheumatic diseases in Turkey.

Rheumatic diseases in Syrian refugee children: a retrospective multicentric study in Turkey.

Since the Syrian civil war in 2011, an estimated number of 3.6 million Syrian refugees crossed into Turkey, and almost half of them were children. The distribution of rheumatic diseases in Syrian refugee children is not known. The aim of this study was to describe the profile of rheumatic diseases in Syrian refugee children living in Turkey. The demographic data, clinical and laboratory findings, medications, complications and outcome results of Syrian refugee children who had visited Pediatric Rheumatology Departments of University of Health Science Kanuni Sultan Süleyman Research and Training Hospital, Ümraniye Research and Training Hospital, Sanliurfa Research and Training Hospital, and Cengiz Gökçek Maternity and Gynecology Hospital between April 1, 2011, and September 1, 2019, were evaluated retrospectively. A total of 151 patients were included in the study. Among them, 51 patients had juvenile idiopathic arthritis (JIA), 49 had familial Mediterranean fever (FMF), 43 had vasculitis, and 8 had connective tissue diseases. Homozygous M694V mutation was the most common mutation among FMF patients. Oligoarticular JIA (41.2%) was the most frequent type of JIA, and enthesitis-related arthritis (ERA) (27.5%) was the second one. The frequency of systemic JIA was 11.8%. One patient with SLE died due to complicated meningitis. This is the first study evaluating the distribution of rheumatic diseases in Syrian refugee children. Clinical follow-up of rheumatologic diseases is difficult in Syrian refugees due to language barriers, social and cultural differences. Health care systems should be well organized to provide appropriate care to asylum seekers.