Mustafa Çakan

Coexistence of early onset sarcoidosis and partial interferon-γ receptor 1 deficiency

Pediatric sarcoidosis comprises a spectrum of childhood granulomatous inflammatory conditions. Pathological hallmark of the disease is granuloma formation that is seen in the affected tissues and almost any organ or system can be involved. There are two forms of pediatric sarcoidosis. One is seen in older children and the clinical picture is very similar to that of adult sarcoidosis and the other one is seen in early childhood. Sarcoidosis in early childhood can be divided as Blau syndrome (familial form) and early onset sarcoidosis (sporadic form). In both of the diseases there is a defect in the NOD2/CARD15 gene. The typical triad of early onset sarcoidosis is polyarthritis, dermatitis and uveitis. Interferon-γ receptor 1 deficiency is caused by defects in the IFNγR1 gene and non-tuberculosis mycobacterial pathogens are the leading causes of infections that start in early childhood. Herein we report a patient who presented with the symptoms of early onset sarcoidosis and also had partial interferon-γ receptor 1 deficiency that presented with BCG-osis. In addition to anti-mycobacterial treatment, methotrexate and prednisolone were used in therapy.

The Turkish Version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR)

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Turkish language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the 3 Likert assumptions, floor/ceiling effects, internal consistency, Cronbach’s alpha, interscale correlations, test–retest reliability, and construct validity (convergent and discriminant validity). A total of 466 JIA patients (13.7% systemic, 40.6% oligoarticular, 22.5% RF negative poly-arthritis, and 23.2% other categories) and 93 healthy children were enrolled in four centres. The JAMAR components discriminated well-healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Turkish version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Does Familial Mediterranean Fever Affect Cognitive Function in Children? Electrophysiological preliminary study

ABSTRACT Objectives: Familial Mediterranean fever (FMF) is a periodic autoinflammatory disease with subclinical inflammation occurring between attacks. The aim of the study was to prospectively evaluate the cognitive function of children diagnosed with FMF that were under colchicine therapy and compare them with healthy controls through electrophysiologically event-related potentials (ERPs) study. Methods: Twelve children with FMF and 12 healthy controls were included in the study. During the electroencephalography recordings, all participants were instructed to discriminate rare stimuli (target stimuli) from frequent stimuli (standard stimuli) by pressing a botton on a mouse immediately following the target stimulus. P300, the cognitive component of ERP, was obtained in response to target stimuli and its amplitude and latency were measured. Results: The amplitude of the P300 of the FMF patients was higher and the latencies of the P300 of the FMF patients were shorter than the amplitudes and latencies of control patients, respectively. The difference between the groups was statistically significant for amplitude but not for latency. Conclusions: Cognitive processing reflecting allocation of attention and visual processing speed seems not to be negatively affected in FMF patients with homozygous M694V mutations undergoing colchicine treatment. As this study is unique in its evaluation of the cognitive function of children with FMF, these findings may be helpful for counseling families and patients affected by the condition.

Two cases of periodic fever syndrome with coexistent mevalonate kinase and mediterranean fever gene mutations

Çakan M, Aktay-Ayaz N, Keskindemirci G, Karadağ ŞG. Two cases of periodic fever syndrome with coexistent mevalonate kinase and Mediterranean fever gene mutations. Turk J Pediatr 2017; 59: 467-470. The periodic fever syndromes are autoinflammatory diseases that present with recurrent fever, serositis and rash. Familial Mediterranean fever is the most common periodic fever syndrome and characterized by recurrent attacks of fever, arthritis, peritonitis, pleuritis that typically last 1-3 days. Hyperimmunoglobulinemia D syndrome is another example of periodic fever syndromes and patients have recurrent fever attacks for 3-7 days accompanied by abdominal pain, rash, vomiting, diarrhea, arthralgia, arthritis, aphthous ulcers, and cervical lymphadenopathy. In some cases the clinical picture of the patient does not fit to one autoinflammatory syndrome because of the digenic inheritance. This may cause to overlap or atypical clinical features or an unexpected response to treatment. Herein we report two cases of hyperimmunoglobulinemia D syndrome that also had MEFV gene mutations and familial Mediterranean fever phenotype.

Subtype frequencies, demographic features, and remission rates in juvenile idiopathic arthritis – 265 cases from a turkish center

Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in children. It is a group of heterogeneous disorders that have chronic arthritis as a common feature. It has a worldwide distribution and many studies have shown that subtype frequencies in JIA seem to be showing geographical distribution. The aim of this study was to define subtype frequencies, demographic features, and the rates of macrophage activation syndrome, uveitis and remission in Turkish JIA patients. The files of all JIA patients (378 cases) that were being followed in Pediatric Rheumatology Clinic of our institution, between May 2010 and February 2016 were reviewed. Two hundred and sixty-five patients were included into the study. Gender, JIA subtype, age at diagnosis, age at the initial symptoms, JIA medications, uveitis presence, JIA status at the time of enrollment were recorded from the files. There were 87 enthesitis related arthritis, 87 oligoarthritis (81 persistent, 6 extended), 36 rheumatoid factor (RF) negative polyarthritis, 35 systemic arthritis, 10 RF-positive polyarthritis, 5 psoriatic arthritis and 5 undifferentiated arthritis cases. Mean age at diagnosis was 9.9 ± 4.9 years and male/female ratio was 1.05. Uveitis was found in 4.5% of the cases. Biologics were used in 26% of the patients. At the time of enrollment, 69% of the patients were under remission while 31% of them were active. Systemic arthritis and persistent oligoarthritis cases were the groups that most commonly achieved remission, while patients with polyarticular involvement, namely RF positive polyarthritis, RF negative polyarthritis and extended oligoarthritis patients were the groups with high number of active patients. In conclusion, JIA is a heterogeneous group of disorder, and differences in subtype frequencies from country to country make it even more heterogeneous disease. Patients with polyarticular involvement may need early and aggressive treatment to control the disease activity.

THU0221 Efficacy of Biological Agents in Colchicine Resistant Children with Fmf

Background Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease diagnosed usually during childhood period. It is managed appropriately with colchicine. Hovewer, even though very rare, there are cases that can not be controlled by colchicine treatment. Ultimate goal of treatment is to control attacks and subside inflammation both during and in between attacks. There are some drugs offered for resistant cases. The anti IL-1 therapy is the most promising one. Objectives This study that is performed in two pediatric rheumatology centers in Turkey is aiming to collect and evaluate the data of children resistant to colcicine treatment and receving anti IL-1 treatment by means of eficacy and safety. Methods Two pediatric rheumatology centers had been involved to the study. The medical data were collected retrospectively. The children had been diagnosed as FMF according to the Tel-Hashomer criteria. Colchicine resistance was defined as having 3 or more attacks despite maximum dose of colchicine treatment regarding to age. The severity of the disease before and after biological treatment was performed by Pras and FMF 50 scores. Results From two pediatric rheumatology centers 26 children were enrolled to the study. The median age at onset of disease was 4 years [(IQR)2–5]. The consanguinity rate was 46.2%. Thirteen of the children had a family member with diagnosed FMF. Only 3 patients had a family history of amyloidosis. Abdominal pain (88.5%) was the most common symptom. The median number of attacks per year was 12 before colchicine treatment, the median attack number dropped to 11 per year after colchicine. The median dose of colchicine before biologic therapy was 1.5 g/day (range 1–1.5). The median duration of colchicine treatment before biologic therapy was 54 months (IQR 23.7–99 months). The median biologic treatment starting age was 11.5 years (range 8.7–16). As biological agent, nineteen patients were started with anakinra, 2 were with etanercept, 5 with canakinumab. The two patients who were under etanercept treatment were switched to anakinra due to lack of effectiveness. Of 19 patients who were commenced anakinra, 12 (63.1%) were switched to canakinumab due to painful injections, lack of effectiveness, allergy and patients choice. There were no switches among canakinumab users. Pras scores had been changed from 10.17 to 6 in anakinra users, from 10 to 6 in canakinumab users. There was no difference of effectiveness between two drugs. The FMF 50 score showed improvement in 14 of 15 anakinra users, 15 of 15 canakinumab users. The difference of scores was not significant between both groups. Conclusions Although colchicine is the main treatment option in FMF, resistant children need additional medications. IL-1 is the major cytokine modulating inflammation in FMF. There are reports pointing out these agents as promising for resistant cases. Our study is the largest cohort of children with resistant FMF under biological treatment. Both anakinra and canakinumab had shown good and similar efficiacy in resistant cases. Long term efficacy and safety evaluations should be done with controlled trials. Disclosure of Interest None declared

AB0972 Rheumatological Signs and Symptoms as the Presenting Manifestations of Childhood Hematological Malignancies

Objectives The earliest manifestations of malignant diseases such as leukemia and lymphoma are diverse. The aim of this study is to determine the characteristics and frequency of rheumatic features as initial symptoms among children diagnosed as acute leukemia and lymphoma. Methods The study is a prospective analysis of 93 children diagnosed as leukemia and lymphoma between 2013-2015. They were diagnosed and treated at pediatric hematology and oncology clinic of Kanuni Sultan Suleyman Research and Training Hospital. Each patient was reviewed for rheumatological symptoms and signs. The evaluation sheet consisted of twelve clinical features and eight signs. Results There were 58 males (62,3%) and 35 females (37,7%) with a total of 93 patients. Acute lymphocytic leukemi (ALL) was diagnosed in 76 (81,8%) patients, acute myeloid leukemia (AML) in 13 (13,9%) patients, and lymphoma (hodgkin and nonhodgkin lymphoma) in 4 (4,3%) patients. Mean age was 78 months (range: 10-204 months). The most common symptoms were fatigue and pallor (51%), fever (25%), bone and leg tenderness (17%). Other symptoms were abdominal pain (9,6%), back pain (7,5%), weight loss (6,4%), arthritis (5,3%), arthralgia without arthritis (5,3%), and chest pain (4,3%). Five patients presenting only with arthritis had the diagnosis of acute lymphocytic leukemia. Four of them were monoarticular and one of them was oligoarticular arthritis. The large joints chiefly knees (2 patients), ankles (2 patients) and elbow (1 patient) were affected. Two patients had been diagnosed as familial mediterranean fever and were under colchicine treatment while they were diagnosed as malignancy. The physical findings included hepatosplenomegaly (36,5%), lymphadenopathy (20%), and petechia, ecchymoses or spontaneous bruising (13,9%). Abnormal laboratory findings in the leukemia group included anemia (65%), thrombocytopenia (76%), leukopenia (25%), leukocytosis (26%), and elevated LDH and ESR levels. The laboratory findings were normal with the exception of one patient in the lymphoma group who only had leukopenia. Conclusions Rheumatological signs and symptoms are not uncommon findings that were faced at hematology-oncology outpatient clinics. Children diagnosed with malignant diseases may present with rheumatological symptoms as initial manifestations. In the differential diagnosis of juvenile rheumatological diseases, malignancies should be kept in mind. Pediatricians facing with atypical symptoms should be aware of these features in malignant diseases. Disclosure of Interest None declared

AB1004 Two Cases of Hyperimmunoglobulin D Syndrome with Mefv Gene Mutations

Background Hyperimmunoglobulin D syndrome (HIDS) is a rare periodic fever syndrome. Fever attacks usually begin during the first year of life and last for 3-7 days. Also arthralgia, arthritis, abdominal pain, mouth ulcers, rash, and cervical lymphadenopathy may be seen during attacks. The disease is caused by mutations in the mevalonate kinase (MVK) gene. There is no proven treatment of the disease, but colchicine and corticosteroids-on-demand are suggested as initial treatments. Familial mediterranean fever (FMF) is the prototype of the periodic fever syndromes and it is caused by mutations in the MEFV gene. Fever and serositis attacks last 1-3 days and colchine is the standart treatment for all cases. Its thought that having more than one periodic fever syndrome gene mutations may alter the phenotype. Here we report two cases of HIDS patients that were also carrying MEFV gene mutations. Case 1 A 3-year-old boy was admitted with the complaint of recurrent fever. The fever had started when he was 4 months old. It was lasting for 4-7 days and was repeating every 1-2 months. In the last 3 attacks the mother was also describing urticarial rash and diarrhea. During febrile periods the patient had extremely high acute phase reactants (CRP: 234 mg/L, ESR: 120 mm/hr). MEFV mutation analysis showed heterozygote R761H mutation and colchicine treatment was started. But under colchicine treatment he had two attacks and the patient was referred to us for consultation. The history of the patient was more suggestive for HIDS and on MVK gene analysis compound heterozygote mutations (N205D and V377I) were found. The patient is being followed for 5 months and currently using colchicine and oral prednisolone during attacks. He had 2 attacks during 5 months that lasted 1 day after prednisolone use and biologic treatment is considered for this case. Case 2 A 3.5-year-old boy was admitted to hospital with the complaints of fever and convulsion. The patient had fever for 3 days and on physical examination he had hepatosplenomegaly, cervical lymphadenopathy and macular rash on the trunk. Medical history was remarkable for recurrent fever attacks that started around one years old. Each attack was lasting for 5-7 days and was repeating every 2-3 months. He also had two simple febrile convulsions during previous attacks. He had anemia (hemoglobin: 8.1 g/dl), thrombocytopenia (platelet: 108.000/mm) and high acute phase reactants (CRP: 182 mg/L, ESR: 100 m/hr). Broad-spectrum antibiotics were initiated after obtaining cultures that did not yield any microorganism. Malignant cells were not observed on bone marrow examination. The fever lasted for 3 days and cytopenias resolved after one week. Mutation analyis for FMF and HIDS were studied and showed heterozygote M680I mutation on MEFV gene and homozygote V377I mutation on MVK gene. Colchicine treatment was started to see the response of the patient to the treatment. The patient is being followed for one year and had only one attack during this period. By colchicine treatment hepatosplenomegaly was regressed and laboratory parameters are normal. As a conlusion, as in our cases, children presenting with symptoms of periodic fever syndromes, more than one diagnosis is possible. Although not all patients with HIDS respond well to colchicine, it should be tried to see the response of the patient. Disclosure of Interest None declared

AB0980 Is There any Difference Regarding to Atopy Between Children with FMF and Healthy Controls

Background Familial Mediterranean fever (FMF) is a periodic autoinflammatory disease presenting with recurrent episodes of fever, abdominal pain, chest pain and arthritis. The MEFV gene encoding the protein pyrin is though to be responsible from the clinical features. It is known that interferon-γ produced by Th1 cells increase the expression of MEFV and promote inflammation while inhibiting IgE dependent Th2 response. Objectives There are only few studies regarding the prevalance of atopy in FMF patients and their results are conflicting. In this study children with the diagnosis of FMF were evaluated for the presence of atopy by comparing with the controls. Methods To this study, 118 children diagnosed as FMF according to Tel-Hashomer criteria and 50 healthy age and sex matched controls were enrolled. None of the children from the control group had taken antihistaminics or other medications 4 weeks before the study and they were not diagnosed for any inflammatory disease. Both of the groups were evaluated for the presence of rhinitis, atopic dermatitis, urticaria and asthma. Laboratory assessment was done by measuring IgA, IgM, IgG, IgE levels, total eosinophil count and by performing skin prick test (SPT) panels for common allergens to children with FMF and healthy controls. Most of the patients had a MEFV gene analysis. Results One hundred eighteen children (61 girls and 57 boys) diagnosed as FMF with a median age of 120 months (range 36-204 months) were compared with 50 healthy controls (31 girls and 19 boys) having a median age of 126 months (range 48-192 months). The median age of onset of symptoms was 54 months (range 4-180 months), median age of diagnosis was 84 months (range 18-192 months) and the median duration of disease was 24 months (range 18-192 months). All the patients were under colchicine treatment. Although there is no statistically significant difference between the personal history of rhinitis, dermatitis, urticaria and asthma between patients and controls, both urticaria and rhinitis were found to be more common in controls. Presence of SPT positivity was not significantly different between patients and controls. While IgA levels were higher in children with FMF, IgE levels were significantly higher in controls (p<0.05). Conclusions FMF is mostly a Th1 driven inflammatory disease while atopy is a Th2 response predominant one. A reduction of atopy had been shown in some inflammatory diseases like rheumatoid arthritis and Behçets disease. Few studies with conflicting results were carried out in patients with FMF. It is important that our study was performed at a larger group of children with FMF. Although statistically not significant, both urticaria and rhinits were found to be less common in children with FMF while atopic dermatitis and asthma were nearly the same in both groups. Lower IgE levels in children with FMF may also mark the role of Th1 in protecting from Th2 driven immune responses. As a last case, significant increase in IgA levels in children with FMF may also be a diagnostic marker for the presence of chronic inflammatory disease. Disclosure of Interest None declared