Evaluation of childhood malignancies presenting with musculoskeletal manifestations from two different divisions: a multicenter study.

BACKGROUND: The aim of the study was to evaluate the approaches of pediatric rheumatologists and pediatric hematologists to patients with similar musculoskeletal (MSK) complaints and to highlight the differences that general pediatricians should consider when referring patients to these specialties. METHODS: This is a cross-sectional study involving the patients who applied to pediatric rheumatology centers with MSK complaints and were diagnosed with malignancy, as well as patients who were followed up in pediatric hematology centers with a malignancy diagnosis, and had MSK complaints at the time of admission. RESULTS: A total of 142 patients were enrolled in the study. Of these patients, 83 (58.4%) applied to pediatric rheumatology centers, and 59 (41.6%) applied to pediatric hematology centers. Acute lymphoblastic leukemia (ALL) was the most common diagnosis among the patients who applied to both centers, with 80 cases (56.3%). The median age of diagnosis was 87 (interquartile range, IQR: 48-140) months. The most common preliminary diagnosis in pediatric rheumatology centers was juvenile idiopathic arthritis (JIA), with 37 cases (44.5%). MSK involvement was mainly seen as arthralgia, and bone pain. While arthralgia (92.7%) was the most common complaint in rheumatology centers, bone pain (88.1%) was more common in hematology centers. The most frequently involved joints were the knee (62.9%), ankle (25.9%), hip (25%), and wrist (14%). The most common laboratory abnormalities were high lactate dehydrogenase (LDH), high C-reactive protein (CRP), anemia, and high erythrocyte sedimentation rate (ESR). Thrombocytopenia, neutropenia, and high LDH were statistically significantly more frequent in patients admitted to hematology centers than in patients admitted to rheumatology centers (p < 0.001, p=0.014, p=0.028, respectively). Patients who applied to rheumatology clinics were found to have statistically significantly higher CRP levels (p=0.032). CONCLUSIONS: Malignancies may present with only MSK system complaints in childhood. Therefore, malignancies should be included in the differential diagnosis of patients presenting with MSK complaints.

Is tear proteome profile a predictor of developing uveitis in ANA-positive patients with oligoarticular juvenile idiopathic arthritis?

PURPOSE: Although less than one-third of anti-nuclear antibody (ANA) positive patients with oJIA develop uveitis, ANA positivity is still the most well-known marker for assessing the risk of uveitis in oligoarticular JIA (oJIA). Therefore, novel biomarkers are needed to better assess the risk of developing uveitis. For this purpose, we performed a comparative tear proteome analysis of uveitis patients to reveal the identity of differentially regulated proteins. DESIGN: Tear samples were collected using the Schirmer strips in 7 oJIA and 7 oJIA patients with uveitis (oJIA-U). All oJIA-U patients had developed bilateral anterior uveitis and were inactive and topical treatment-free. METHODS: The nHPLC LC-MS/MS system was used for protein identification and label-free proteome comparisons. The PANTHER and STRING analyses were carried out using UniProt accession numbers of the identified proteins. RESULTS: Patient characteristics, e.g., age, gender, disease duration, and treatments were similar. For protein identification, three different databases were searched. Twenty-two, 147, and 258 database searches, respectively. Of these, 15 were common to all three proteome databases. Of these 15 proteins, 10 proteins were upregulated, and 2 were downregulated, based on the twofold regulation criteria. The upregulated proteins were, namely, cystatin-S, secretoglobin family 1D member, opiorphin prepropeptide, mammaglobin-B, lysozyme C, mesothelin, immunoglobulin kappa constant, extracellular glycoprotein lacritin, beta-2-microglobulin, and immunoglobulin J chain. The downregulated proteins were dermcidin and prolactin-inducible protein. Among the differentially regulated proteins, cystatin-S was the most regulated protein with an 18-fold upregulation ratio in tear samples from uveitis patients. CONCLUSION: Here, the identities and regulation ratios of several proteins were revealed when tear samples from uveitis patients were compared to patients without uveitis. These proteins are putative biomarkers for assessing uveitis risk and require further attention.

Inflammatory comorbidities in the largest pediatric Familial Mediterranean fever cohort: a multicenter retrospective study of Pediatric Rheumatology Academy (PeRA)-Research Group (RG).

AIM: The aim of this study was to investigate the frequency and type of FMF-associated inflammatory diseases in a large FMF pediatric patients and to compare them to those FMF patients without concomitant inflammatory diseases. MATERIALS AND METHODS: Familial Mediterranean fever patients enrolled in the Pediatric Rheumatology Academy (PeRA)-Research Group (RG) were included. The patients were divided into two groups according to concomitant inflammatory disease as FMF patients who had a concomitant inflammatory disease (group 1) and FMF patients who did not have a concomitant inflammatory disease (group 1). The clinical findings and treatments were compared between the two groups. RESULTS: The study group comprised 3475 patients with FMF. There were 294 patients (8.5%) in group 1 and 3181 patients (91.5%) in group 2. Juvenile idiopathic arthritis (n = 136) was the most common accompanying inflammatory disease. Arthritis, M694V homozygosity, and the need for biological therapy were more frequently observed in Group 1 (p < 0.05). Fever and abdominal pain were more frequently detected in Group 2 (p < 0.05). FMF patients with concomitant inflammatory diseas more frequently demonstrated colchicine resistance. There were no significant differences in the median attack frequency, chest pain, amyloidosis, erysipelas-like erythema, or family history of FMF between the two patient groups. CONCLUSION: To the best of our knowledge, this is the largest pediatric cohort reviewed to date. FMF patients may have different clinical profiles and colchicine responses if they have with concomitant inflammatory diseases. Key points • FMF is associated with some inflammatory comorbidities diseases. • To the best of our knowledge, this is the largest cohort evlauated pediatric FMF associated inflammatory comorbidities diseases reviewed to date.

Splenic Artery Embolization in a Patient With Intracranial Hemorrhage Due to Refractory Persistent Immune Thrombocytopenia.

BACKGROUND: Managing intracranial bleeding in patients with refractory immune thrombocytopenia is difficult. OBSERVATION: A 16-year-old female refractory to prednisolone, intravenous immunoglobulin, eltrombopag, and cyclosporin exhibited heavy menstrual bleeding requiring packed red blood cell transfusions. Autoimmune antibodies were detected, indicating of lupus, and hydroxychloroquine sulfate was administered. In month 6 following the diagnosis, the patient presented with intracranial hemorrhage. Splenic artery embolization promptly increased platelets, and the patient was discharged without any neurological sequela. In month 5 of embolization, the patient's platelet count continued to exceed 300,000/µL without any medical treatment. CONCLUSIONS: Splenic artery embolization is a life-saving procedure in refractory immune thrombocytopenia.

The Effect of Interleukin-1 Antagonists on Brain Volume and Cognitive Function in Two Patients With Megalencephalic Leukoencephalopathy With Subcortical Cysts.

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy characterized by early-onset macrocephaly and progressive white matter vacuolation. The MLC1 protein plays a role in astrocyte activation during neuroinflammation and regulates volume decrease following astrocyte osmotic swelling. Loss of MLC1 function activates interleukin (IL)-1ß-induced inflammatory signals. Theoretically, IL-1 antagonists (such as anakinra and canakinumab) can slow the progression of MLC. Herein, we present two boys from different families who had MLC due to biallelic MLC1 gene mutations and were treated with the anti-IL-1 drug anakinra. METHODS: Two boys from different families presented with megalencephaly and psychomotor retardation. Brain magnetic resonance imaging findings in both patients were compatible with the diagnosis of MLC. The diagnosis of MLC was confirmed via Sanger analysis of the MLC1 gene. Anakinra was administered to both patients. Volumetric brain studies and psychometric evaluations were performed before and after anakinra treatment. RESULTS: After anakinra therapy, brain volume in both patients decreased significantly and cognitive functions and social interactions improved. No adverse effects were observed during anakinra therapy. CONCLUSIONS: Anakinra or other IL-1 antagonists can be used to suppress disease activity in patients with MLC; however, the present findings need to be confirmed via additional research.

Should children with psoriasis be consulted to a rheumatologist? Result from pediatric rheumatology-dermatology collaboration.

OBJECTIVE: The objectives of this study were to determine the musculoskeletal (MSK) conditions associated with pediatric psoriasis (Pso) and to evaluate the thickness of Achilles tendon of children with Pso and healthy controls (HCs). METHODS: Pso patients who were followed-up in dermatology outpatient clinic were referred to a pediatric rheumatology center. All patients and healthy peers were evaluated with standardized forms. Both patients and controls underwent ultrasonographic evaluation for Achilles tendon thickness. RESULTS: A total of 55 pediatric Pso and 46 healthy children were included in the study. Of patients with Pso 56.4% had arthralgia, 25.5% had lower back pain, 18.2% had heel pain, 12.7% had hip pain, and 10.9% described morning stiffness. Arthritis was detected in 7.3%, sacroiliac tenderness in 12.7%, and enthesitis in 9.1% of the patients. Arthralgia, lower back pain, and heel pain were significantly frequent in Pso group than healthy children median left and right Achilles tendon thicknesses of Pso patients who were significantly greater than that of HCs prevalence of psoriatic arthritis (PsA) among Pso patients was 7.3%. CONCLUSION: Evaluation of a child with Pso regularly for the MSK complaints is critical for the early recognition of PsA. Ultrasonography is a useful technique for screening Pso patients for early detection of enthesopaty.

Cardiovascular manifestations of monogenic periodic fever syndromes.

Periodic fever syndromes (PFS) are a group of autoinflammatory diseases characterized by repeated febrile episodes and systemic inflammation. The most common monogenic periodic fever syndromes are familial Mediterranean fever, mevalonate kinase deficiency/hyper immunoglobulin D syndrome, cryopyrin-associated periodic syndrome, and tumor necrosis factor receptor-associated periodic syndrome. Although fever is the predominant feature of PFS, other systems, including the cardiovascular system, may be involved in the disease process. This review focuses on cardiovascular risks and issues in monogenic PFS. Cardiovascular involvement may occur as a disease manifestation, association, or result of complications or a drug's adverse effects in monogenic PFS. Pericarditis seems to be a feature of PFS. Patients with recurrent pericarditis or pericarditis resistant to conventional treatment should be evaluated for PFS. Amyloidosis is the most severe complication of PFS, increasing the risk of cardiac morbidity. Furthermore, ongoing inflammation may result in early atherosclerosis. Therefore, assessing cardiovascular risks in PFS patients should be considered a part of routine care. Key points • Pericarditis is the most common cardiac involvement of monogenic periodic fever syndromes (PFS), while some forms may present with myocarditis. • Amyloidosis, the most significant complication of PFS, may lead to deterioration in cardiac functions. • Ongoing inflammation in PFS may result in endothelial dysfunction and atherosclerosis. • Effective control of inflammation and reducing concomitant risk factors such as obesity, diabetes mellitus, and hypertension could improve cardiovascular outcomes in PFS patients.

Is it all about age? Clinical characteristics of Kawasaki disease in the extremely young: PeRA research group experience.

OBJECTIVES: In the evaluation of children with Kawasaki disease (KD), the age of onset is important and complications may occur if the distinctive features are not assessed accordingly. The objective of the study is to define the clinical and laboratory presentations and treatment outcomes of KD in infants ≤6 months of age compared to those >6 months multicentrically. METHODS: This retrospective study reviewed the medical records of the patients diagnosed with KD and followed up between January 2009 and January 2019. RESULTS: A total of 204 KD patients were enrolled and grouped according to age as Group I (≤6 months, n = 31) and Group II (>6 months, n = 173). Except for cervical adenopathy (19.3% vs. 47.4%, p = 0.03), the major clinical manifestations of KD were similar between groups I and II. However, the frequency of incomplete and atypical KD was higher in Group I (38.7% vs. 24.8%, p = 0.04, 38.7% vs. 8.1% p < 0.001, respectively). Clinical features such as vomiting/diarrhea (19.3% vs. 1.1% p < 0.001), aseptic meningitis (19.3% vs. 2.3%, p = 0.001) were more common in Group I. Percentage of neutrophils (45.5 vs. 36, p = 0.004) and hemoglobin levels (8 vs. 10.5 gr/dL, p = 0.02) were statistically lower and platelet count (737,000 vs 400,000/mm3, p = 0.004) was statistically higher in group I. Coronary artery lesions (CALs) were more common in Group I (48% vs. 20%, p < 0.001). Harada and Kobayashi scores appear to be effective in predicting coronary artery lesions (CALs) and IVIG resistance in the entire cohort. There was no diagnostic delay in group I (5.5 vs 6.5 days, p = 0.88). CONCLUSIONS: Since clinical presentations and laboratory features of KD may vary with age, and the frequency of atypical and incomplete presentations is high, awareness of KD in young children should be raised among pediatricians.

Toward the integration of biosimilars into pediatric rheumatology: adalimumab ABP 501 experience of PeRA research group.

OBJECTIVES: To review the real-life data, to provide an input to the literature concerning treatment of juvenile idiopathic arthritis (JIA) with adalimumab (ADL) biosimilar. METHOD: This multi-centric retrospective study was conducted among children with JIA, followed up for at least 24-weeks from the initiation of ADL biosimilar (ABP 501) treatment. Adverse events and alterations in disease activity scores were figured out. RESULTS: The median age of the group was 15.5 (5-18) years. JIA categories were oligoarticular (n =12), enthesitis-related (ERA) (n=24), psoriatic (PsA) (n=6), and polyarticular (n=4). Uveitis was detected at the initiation of the disease (n=3), during the disease course (n=5), or before the diagnosis (n=1). The first-line treatment preferences were ADL biosimilar (n=37) and etanercept (n=9). On the 6th month of ABP 501, 40 (86.9%) patients had achieved complete remission. Six patients (1 PsA, 1 polyarticular JIA, and 4 ERA) had ongoing active arthritis. Furthermore, all except one of the patients had remission of ophthalmologic findings. No life-threatening adverse events were observed. CONCLUSIONS: ABP 501 has a gradual increase in prescription in pediatric rheumatology. Real-life data of the cohort announce that ADL biosimilar is a suitable and effective treatment option for patients with JIA in case of indication.

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.

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.

Frequency of juvenile idiopathic arthritis and associated uveitis in pediatric rheumatology clinics in Turkey: A retrospective study, JUPITER.

BACKGROUND: Juvenile idiopathic arthritis (JIA), is the most common pediatric rheumatologic disorder with unknown etiology. Currently, no population-based data are available regarding the distribution of categories and frequency of uveitis in patients with JIA in Turkey. The purpose of this study was to evaluate the frequency of JIA-associated uveitis (JIAU) and distribution of JIA categories in a Turkish JIA cohort. METHODS: This was a retrospective study of 500 randomized patients in four pediatric rheumatology clinics in Turkey. RESULTS: Oligoarticular JIA (oJIA) was the most common JIA disease category in this study cohort (38.8%). The frequencies of the other categories were as follows: enthesitis-related arthritis (ERA), 23.2%; rheumatoid factor (RF)-negative polyarthritis, 15.6%; systemic arthritis, 12.2%; juvenile psoriatic arthritis, 5.2%; undifferentiated arthritis, 2.8%; and RF-positive polyarthritis, 2.2%. JIA-associated uveitis was observed in 6.8% of patients at a mean (Standard Deviation, SD) age of 9.1 (3.8) years over a mean JIA disease duration of 4 (1.9) years. Uveitis developed after joint disease, with a mean (SD) duration of 1.8 (1.9) years. Patients with oJIA had the highest rate of uveitis (12.9%) followed by patients with ERA (5.2%) and polyarticular RF-negative disease (3.8%). Compared with persistent oJIA, the extended oJIA category had a > 3-fold higher risk of uveitis (11.3% vs 27.7%; odds ratio, 3.38 [95% Confidence Interval, 1.09-10.4]). The most frequently administered drug after development of uveitis was tumor necrosis factor-alpha inhibitors (38.2%). Five patients (14.7%) had uveitis-related complications that required surgical intervention. CONCLUSIONS: Turkish pediatric patients with JIA experience a lower frequency of oJIA and higher frequency of ERA than their white European counterparts; the occurrence of uveitis is also somewhat lower than expected. Geographic and ethnic factors may affect these differences and need further investigation.

Neuroimaging of Children With Takayasu Arteritis.

OBJECTIVE: Takayasu arteritis is a rare granulomatous chronic vasculitis that affects the aorta and its main branches. Neurologic manifestations can accompany the disease; however, there is no study on neuroimaging in children with Takayasu arteritis. Therefore, we aimed to evaluate cranial magnetic resonance imaging (MRI) in pediatric Takayasu arteritis patients. MATERIALS AND METHODS: Demographic, clinical, and laboratory data were obtained retrospectively. RESULTS: The study included 15 pediatric Takayasu arteritis patients. All patients presented with constitutional symptoms. Additionally, 6 patients suffered from headache, 2 had syncope, 1 had loss of consciousness, and 1 had convulsion. All patients underwent cranial and diffusion MRI a median 12 months after diagnosis. Cranial MRI findings were normal in 12 patients, whereas 3 patients had abnormal findings, as follows: stenosis in the M1 and M2 segments of the left middle cerebral artery (n = 1); diffuse thinning of the right internal carotid, middle cerebral, and right vertebral and basilar artery (n = 1); as a sequela, areas of focal gliosis in both the lateral ventricular and posterior periventricular regions (n = 1). Among these 3 patients, 1 had no neurologic complaints. CONCLUSION: Abnormal MRI findings can be observed in pediatric Takayasu arteritis patients, even those that are asymptomatic; therefore, clinicians should carefully evaluate neurologic involvement in all pediatric Takayasu arteritis patients.

Real-Life Data From the Largest Pediatric Familial Mediterranean Fever Cohort.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease manifesting phenotypic heterogeneity. It is a clinically diagnosed disease supported by MEditerranean FeVer (MEFV) gene mutation analysis. However, the phenotype-genotype correlation is not yet established clearly. We aimed to determine the clinical findings, phenotype-genotype correlation, and treatment outcomes within a large pediatric FMF cohort. The medical charts of children with FMF who were diagnosed and followed up at the eight pediatric rheumatology units were reviewed retrospectively. All patients in the cohort were analyzed for sequence variants in exon 2,3,5 and 10 of the MEFV gene. Patients without any mutations or with polymorphisms including R202Q were excluded. A total of 3,454 children were involved in the study. The mean ± standard deviation of current age, age at symptom onset, and age at diagnosis were 12.1 ± 5.2, 5.1 ± 3.8, and 7.3 ± 4.0 years, respectively. Of 3,454 patients, 88.2% had abdominal pain, 86.7% had fever, 27.7% had arthritis, 20.2% had chest pain, 23% had myalgia, and 13.1% had erysipelas-like erythema. The most common MEFV mutation patterns were homozygous (32.5%) and heterozygous (29.9%) mutations of exon 10. Homozygous M694V was present in 969 patients (28.1%). Allele frequencies of common mutations were M694V (55.3%), M680I (11.3%), V726A (7.6%), and E148Q (7.2%). Children carrying homozygous or compound heterozygous exon 10 mutations had an earlier age of disease onset (4.6 vs. 5.6 years, p = 0.000) and a higher number of attacks per year (11.1 vs. 9.6, p = 0.001). Although 8% of the patients had a family history of amyloidosis, 0.3% (n = 11) had the presence of amyloidosis. M694V homozygosity was detected in nine patients who developed amyloidosis. Colchicine resistance was present in 4.2% of our patients. In this largest pediatric cohort reviewed and presented to date, patients with exon 10 mutations, particularly the M694V homozygous mutation, have been demonstrated earlier disease onset, annual attack count, and more frequent colchicine-resistant cases. Although E148Q is considered as a polymorphism in some populations, it was identified as a disease-causing mutation in our cohort. Secondary amyloidosis is still happening in adults however, it is extremely rare among children, presumably due to increased awareness, tight control, and the availability of anti-IL1 agents in colchicine-resistant cases.

Systemic lupus erythematosus complicated with Castleman disease: a case-based review.

Systemic lupus erythematosus (SLE) is a complex, chronic, multi-systemic autoimmune disease, characterized by miscellaneous clinical findings. Castleman disease (CD) is a rare lymphoproliferative disorder that may present with systemic symptoms. Herein, a SLE case complicated with CD is reported by comparing her clinical findings with previously reported patients. We reviewed the literature regarding cases of "Castleman disease" and "Systemic lupus erythematosus" by searching medical journal databases in MEDLINE, EMBASE, Scopus, and Web of Science. A case of a 16-year-old girl with SLE who had intraabdominal lymphadenopathy detected both by ultrasonography and abdominal magnetic resonance imaging is presented. The excision of the lymph node was performed by pediatric surgeons. Histopathological examination was compatible with CD. Hydroxychloroquine and steroid treatments were started after the operation. She achieved remission in 3 months. In the literature research, we found 10 articles describing 17 patients. To our best of knowledge, the presented case was the third pediatric case in the literature with SLE and coexistent CD. This case report and literature review suggests that CD should be considered while evaluating and following patients with autoimmune diseases.

Comparison of the clinical diagnostic criteria and the results of the next-generation sequence gene panel in patients with monogenic systemic autoinflammatory diseases.

INTRODUCTION/OBJECTIVES: The clinicians initially prefer to define patients with the systemic autoinflammatory disease (SAID)'s based on recommended clinical classification criteria; then, they confirm the diagnosis with genetic testing. We aimed to compare the initial phenotypic diagnoses of the patients who were followed up with the preliminary diagnosis of a monogenic SAID, and the genotypic results obtained from the next-generation sequence (NGS) panel. METHOD: Seventy-one patients with the preliminary diagnosis of cryopyrin-associated periodic fever syndrome (CAPS), mevalonate kinase deficiency (MKD), or tumor necrosis factor-alpha receptor-associated periodic fever syndrome (TRAPS) were included in the study. The demographic data, clinical findings, laboratory results, and treatments were recorded. All patients were examined by NGS panel analysis including 16 genes. The genetic results were compared with the initial Federici score to determine whether they were compatible with each other. RESULTS: Thirty patients were initially classified as MKD, 22 as CAPS, and 19 as TRAPS. The frequency of clinical manifestations was urticarial rash 57.7%, diarrhea 49.2%, abdominal pain 47.8%, arthralgia 45%, oral aphthae 43.6%, myalgia 32.3%, tonsillitis 28.1%, and conjunctivitis 25.3%, respectively. After NGS gene panel screening, 13 patients were diagnosed with CAPS, 8 with MKD, 7 with familial Mediterranean fever, 5 with TRAPS, and 2 with NLRP12-associated periodic syndrome. The remaining 36 patients were genetically identified as undefined SAID since they were not classified as one of the defined SAIDs after the result of the NGS panel. CONCLUSIONS: We have demonstrated that clinical diagnostic criteria may not always be sufficient to establish the correct diagnosis. There is still low accordance between clinical diagnoses and molecular analyses. In the case of a patient with a preliminary diagnosis of a monogenic SAID with the negative result of target gene analysis, other autoinflammatory diseases should also be kept in mind in the differential diagnosis. Key Points • Monogenic autoinflammatory diseases can present with different clinical manifestations. • The clinical diagnostic criteria may not always be sufficient to reach the correct diagnosis in autoinflammatory diseases. • In the case of a patient with a preliminary diagnosis of a monogenic SAID with the negative result of target gene analysis, other autoinflammatory diseases should be kept in mind in the differential diagnosis.

Sacroiliitis in children and adolescents with familial Mediterranean fever

Abstract Background: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent episodes of fever and serositis. Sacroiliitis can be observed in some FMF patients. This study aimed to compare the demographic, clinical, and laboratory findings, and treatment in children with FMF and sacroiliitis, and children with juvenile spondyloarthropathy (JSpA). Methods: In total, 1687 pediatric FMF patients that were followed-up between May 2010 and June 2020 were evaluated retrospectively. Among them, those with sacroiliitis ( n = 63) were included in the study and compared to patients with JSpA ( n = 102). Results: The study included 63 FMF patients with sacroiliitis (38 males [60.3%] and 25 females [39.7%]) with a mean age of 15.2 ± 4.1 years. Mean age at symptom onset was 7.2 ± 5.05 years and mean age at diagnosis was 9.74 ± 4.67 years. The most common mutation in the FMF patients was M694V/M694V ( n = 22). Patients were diagnosed with sacroiliitis with a mean of 12 months (range: 6-36 months) after the diagnosis of FMF. Among the FMF patients, 28 (44.4%) had enthesitis, 23 (36.5%) had heel pain, and 11 (17.4%) had low back pain. The study also included 102 JSpA patients (90 males [88.2%] and 12 females [11.8%]). Mean age of patients with JSpA was 16.1 ± 2.8 years. As compared to 102 JSpA patients, patients with FMF and sacroiliitis had higher acute phase reactants, whereas HLA- B27 positivity rate was lower. In addition, axial involvement rate was higher in the JSpA patients. Conclusion: Sacroiliitis is a common co-morbidity in FMF patients. The phenotypic features of these patients are different from patients with JSpA.

A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder associated with ADA2 mutations. We aimed to investigate the characteristics and ADA2 enzyme activities of patients with DADA2 compared to non-DADA2 patients. METHODS: This is a descriptive study of 24 patients with DADA2 who were admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments of Hacettepe University. All ADA2 exons were screened by Sanger sequencing. Serum ADA2 enzyme activity was measured by modified spectrophotometric method. RESULTS: Twenty-four patients with DADA2 were included: 14 with polyarteritis nodosa (PAN)-like phenotype (Group 1); 9 with Diamond-Blackfan anemia (DBA)-like features, and 1 with immunodeficiency (Group 2). Fourteen PAN-like DADA2 patients did not have the typical thrombocytosis seen in classic PAN. Inflammatory attacks were evident only in Group 1 patients. Serum ADA2 activity was low in all patients with DADA2 except one, who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 activities between PAN-like and DBA-like patients. In DADA2 patients with one ADA2 mutation, serum ADA2 activities were as low as those of patients with homozygote DADA2. ADA2 activities were normal in non-DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and the catalytic domain in Group 2 patients. CONCLUSION: We suggest assessing ADA2 activity along with genetic analysis because there are patients with one ADA2 mutation and absent enzyme activity. Our data suggest a possible genotype-phenotype correlation in which dimerization domain mutations are associated with PAN-like phenotype, and catalytic domain mutations are associated with hematological manifestations.

A clinical score to guide in decision making for monogenic type I IFNopathies.

OBJECTIVE: To develop a set of clinical criteria that identifies patients with a potential autoinflammatory IFNopathy. METHODS: Based on a literature review, a set of clinical criteria identifying genetically confirmed monogenic IFNopathies was selected. For validation, the clinical score was assessed in healthy controls (HCs) and 18 disease controls, including 2 known autoimmune IFNopathies, juvenile systemic lupus erythematosus (JSLE, n = 4) and dermatomyositis (JDM, n = 4); adenosine deaminase 2 deficiency (DADA2, n = 4); and oligoarticular juvenile idiopathic arthritis (oJIA, n = 6). We assessed an IFN score (IRG-S) in whole blood by NanoString using a previously published 28-gene-IRG-S and a reduced 6-gene-IRG-S. RESULTS: The 12 patients with a possible IFNopathy had higher clinical scores (3-5) than the patients with sJLE, JDM, DADA2, and oJIA and in HCs. Both the 28-IRG-S and 6-IRG-S were significantly higher in the autoinflammatory IFNopathy patients compared to HCs and oJIA and DADA2 patients but not different from patients with JSLE and JDM. Subsequently, genetic analysis revealed mutations in genes previously reported in genes related to the IFN pathway in 9 of the 12 patients. CONCLUSION: We developed a clinical score to identify patients with possible autoinflammatory IFNopathies. A clinical score was associated with a high IRG-S and may serve to identify patients with an autoinflammatory IFNopathy.