Practical Approach to Diagnosis and Management of IL-1-Mediated Autoinflammatory Diseases (CAPS, TRAPS, MKD, and DIRA).

Systemic autoinflammatory diseases (SAIDs) are a group of rare genetic and nongenetic immune dysregulatory disorders associated with high morbidity and mortality if left untreated. Therefore, early diagnosis and initiation of targeted treatment is vital in SAID patients to control the disease activity and prevent long-term immune-mediated damage. A specific group of genetically defined SAIDs is associated with increased inflammasome-mediated production of active interleukin (IL)-1. Even though progress in immunobiology and genetics has brought forth diagnostic tools and novel treatments that have been described in the literature extensively, many challenges remain in the clinical setting. Some challenges that health care providers may face on a day-to-day basis include the requirement of a multidisciplinary approach due to the complexity of these diseases, limited evidence-based treatment options, and barriers to access available therapies. Primarily, IL-1 inhibitors anakinra, canakinumab, and rilonacept are used to control the inflammation in these patients, with the goal of achieving sustainable remission. Recently published provisional points to consider from the European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) provide diagnosis, management, and monitoring recommendations for four IL-1-mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and deficiency of the IL-1 receptor antagonist (DIRA). The goal of this paper is to aid health care professionals by providing a practical approach to diagnosis and management of these four IL-1 mediated SAIDs on the basis of the recent EULAR/ACR recommendations.

Hematologic abnormalities in Aicardi Goutières Syndrome.

BACKGROUND: Because of the broad clinical spectrum, heritable autoinflammatory diseases present a management and therapeutic challenge. The most common genetic interferonopathy, Aicardi Goutières Syndrome (AGS), is associated with early onset neurologic disability and systemic inflammation. The chronic inflammation of AGS is the result of dysregulation of interferon (IFN) expression by one of nine genes within converging pathways. While each AGS subtype shares common features, distinct patterns of severity and potential for systemic complications amongst the genotypes are emerging. Multilineage cytopenias are a potentially serious, but poorly understood, complication of AGS. As immunomodulatory treatment options are developed, it is important to characterize the role of the disease versus treatment in hematologic abnormalities. This will allow for better understanding and management of cytopenia. METHODS: In total, 142 individuals with molecularly-confirmed AGS were included. Information on genotype, demographics, and all available hematologic laboratory values were collected from existing medical records. As part of a clinical trial, a subset of this cohort (n = 52) were treated with a janus kinase inhibitor (baricitinib), and both pre- and post-treatment values were included. Abnormal values were graded based on Common Terminology Criteria for Adverse Events (CTCAE v5.0), supplemented with grading definitions for thrombocytosis, and were compared across genotypes and baricitinib exposure. RESULTS: In total, 11,184 laboratory values were collected over a median of 2.54 years per subject (range 0-22.68 years). To reduce bias from repeated sampling within a limited timeframe, laboratory results were restricted to the most abnormal value within a month (n = 8485). The most common abnormalities were anemia (noted in 24% of subjects prior to baricitinib exposure), thrombocytopenia (9%), and neutropenia (30%). Neutropenia was most common in the SAMHD1 cohort and increased with baricitinib exposure (38/69 measurements on baricitinib versus 14/121 while not on baricitinib). Having an abnormality prior to treatment was associated with having an abnormality on treatment for neutropenia and thrombocytopenia. CONCLUSION: By collecting available laboratory data throughout the lifespan, we were able to identify novel patterns of hematologic abnormalities in AGS. We found that AGS results in multilineage cytopenias not limited to the neonatal period. Neutropenia, anemia, and thrombocytopenia were common. Moderate-severe graded events of neutropenia, anemia, and leukopenia were more common on baricitinib, but rarely of clinical consequence. Based on these results, we would recommend careful monitoring of hematologic parameters of children affected by AGS throughout the lifespan, especially while on therapy, and consideration of AGS as a potential differential diagnosis in children with neurologic impairment of unclear etiology with hematologic abnormalities. Trial registration ClinicalTrials.gov Identifier: NCT01724580 ClinicalTrials.gov Identifier: NCT03921554.

Number of Episodes Can Be Used as a Disease Activity Measure in Familial Mediterranean Fever.

Objective: To evaluate the number of episodes in the past 12 months as an indicator of the overall disease activity status in Familial Mediterranean fever (FMF). Methods: In this cross-sectional study, patients were recruited from tertiary pediatric hospitals. Demographic data, main clinical symptoms of the episodes, treatment modalities, and genetic mutations were recorded. The patients were grouped as no episodes (Group 1), 1-4 episodes (Group 2), and more than 4 episodes (Group 3) according to the number of episodes in the past 12 months. The Pediatric Quality Life Inventory (PedsQL), the Children's Depression Inventory (CDI), and the Wong-Baker FACES Pain Rating Scale (FACES) scores were compared between groups. Concurrent validity between the number of episodes and the patient-reported outcome measures (PROMs) was assessed using Spearman's rank correlation coefficient (ρ). Results: A total of 239 patients were included. There were 74 patients (31%) in Group 1, 99 (41.4%) in Group 2, and 66 (27.6%) in Group 3. Groups were similar according to age, age at diagnosis, gender, consanguinity, family history, history of amyloidosis, clinical symptoms, and in terms of allele frequency (p > 0.05). According to PROMs completed by parents, moderate correlations were found between the number of episodes and the PedsQL score (ρ = -0.48; 95% CI = -0.58 to -0.35, p < 0.001) and between the number of episodes and the Wong-Baker FACES score (ρ = 0.47, 95% CI = 0.35-0.57, p < 0.001). Conclusion: The number of episodes was positively and moderately correlated with patient- and parent-reported outcomes in our cohort. The number of episodes in patients with FMF can be used as a single measure to assess disease activity.

Evaluation of E148Q and Concomitant AA Amyloidosis in Patients with Familial Mediterranean Fever.

The aim of the study was to compare the clinical phenotype of patients with familial Mediterranean fever (FMF)-related AA amyloidosis, according to the age of FMF diagnosis and E148Q genotype. Patients with biopsy-confirmed FMF-related AA amyloidosis were included in the study. Tel-Hashomer criteria were applied in the diagnosis of FMF. All patients had detailed baseline assessment of clinical features, renal functions, genetic testing, histopathological diagnosis of amyloidosis, and treatment received. Multiple comparisons were performed according to the age of diagnosis, disease phenotype, mutation, and mortality. Our study included 169 patients with a diagnosis of AA amyloidosis. There were 101 patients diagnosed with FMF < 18 years of age and 68 patients diagnosed who were ≥18 years of age. The three most common clinical manifestations were fever (84.6%), abdominal pain (71.6%), and arthritis (66.9%). The most common allele among FMF patients was M694V (60.6%), followed by E148Q (21.4%), and M680I (10.3%). The most frequent genotypes were M694V/M694V (45.0%), M694V/E148Q (14.8%), and E148Q/E148Q (11.2%) among 169 patients in our cohort. During the follow-up period, 15 patients (10 male, 5 female) died, of whom 14 had M694V homozygous genotype and one was homozygous for E148Q. Clinicians should be aware of patients with homozygous E148Q genotype for close monitoring and further evaluation. The possible relationship between E148Q and AA amyloidosis needs to be confirmed in other ethnicities.

Oral health status in children with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory disease. We aimed to investigate the oral health status and oral hygiene habits in children with FMF. METHODS: In this cross-sectional study, 199 children with FMF, aged between 3-18 years, were included. Demographic findings and oral hygiene habits of children were questioned by face-to-face interview. Oral health status of patients was evaluated using decay-missing-filled index [DMFT (decay-missing-filled teeth), DMFS (decay-missing-filled teeth) for permanent; dmft, dmfs for primary teeth], the International Caries Detection and Assessment System (ICDAS-II) index, PUFA / pufa index [the presence of severely decayed teeth with visible pulpal involvement (P/p), ulceration caused by dislocated tooth fragments (U/u), fistula (F/f) and abscess (A/a)], gingival (GI) and plaque index (PI). In addition to these, occlusion, oral soft and hard tissues were examined. RESULTS: One-hundred-nine (54.8%) of children had at least one decayed permanent tooth and 81.2% of children had at least one decayed primary tooth. The mean DMFT was 1.91±2.45, DMFS was 3.1±4.49, dmft was 3.95±3.54, dmfs was 8.62±8.88, PI was 1.17±0.44, GI was 0.85±0.39. Aphthous mouth ulcer occurred in 19 (9.5%) patients. Recurrent aphthous mouth ulcers were more frequent among patients with one exon-ten and one exon-two mutations than patients with one exon-10 mutation, two exon-ten mutations, or two exon-2 mutations (61.1% vs. 47.9%, 26.1%, 20%, respectively p < 0.001). Tooth decay was more frequent among patients who had attacks in the last six months than those who did not have any attacks during the last six months (97.4% vs. 87.7%, p=0.017). CONCLUSION: Dental caries and periodontal disease, which are public health problems, were seen at a high percentage of children with FMF in our study.

Comorbidities in familial Mediterranean fever: analysis of 2000 genetically confirmed patients.

OBJECTIVES: FMF is the most common periodic fever syndrome, characterized by recurrent episodes of fever and serosal inflammation accompanied with high acute phase reactants. The analysis of possible comorbidities is important to understand the impact of these conditions on clinical care and whether they share a common aetiological pathway. In this study, we aimed to evaluate the comorbidities associated with FMF patients in a large genetically diagnosed cohort. METHODS: We retrospectively evaluated the medical and genetic records of FMF patients who were followed up by rheumatologists in Hacettepe University for 15 years. The FMF patients who had homozygous or compound heterozygous mutations were included in the study. Comorbidities associated with FMF were divided into three groups: (i) comorbidities directly related to FMF, (ii) comorbidities due to increased innate inflammation, and (iii) comorbidities that were regarded as being incidental. RESULTS: A total of 2000 patients with a diagnosis of FMF were enrolled in the study. Among them 636 were children (31.8%) and M694V was the most common mutation in patients with associated inflammatory conditions. The frequency of AS, Iga Vasculitis (Henoch-Schönlein purpura), juvenile idiopathic arthritis, polyarteritis nodosa, multiple sclerosis and Behçet's disease were increased in patients with FMF when compared with those in the literature. CONCLUSION: This study represents the largest genetically confirmed cohort and compares the frequencies with existing national and international figures for each disease. The increased innate immune system inflammation seen in FMF may be considered as a susceptibility factor since it predisposes to certain inflammatory conditions.

Severe hypersensitivity reactions to biological drugs in children with rheumatic diseases.

BACKGROUND: Hypersensitivity reactions (HSR) to biologic drugs (BD) may limit their use in children with rheumatic diseases. We aimed to analyze the incidence and clinical characteristics of immediate type I (IgE/non-IgE) hypersensitivity reactions to BD and the risk factors for these reactions. METHODS: Children with rheumatic diseases using BD who were evaluated in the pediatric allergy department for possible drug hypersensitivity reaction (DHR) due to BD or any other drug were included in the study. RESULTS: One hundred and twenty-eight children (49.2% boys; 14.6 years [9.9-16.9 years] with juvenile idiopathic arthritis [58%], familial Mediterranean fever [14%], vasculitis [14%], and other diseases [14%]) had used eight different BD with 32 494 infusions/injections. Fifteen patients were evaluated for DHR [injection-site reactions [n = 4], adverse events [n = 2], drug hypersensitivity other than BD [n = 3], and immediate BD hypersensitivity [n = 6]). The incidence of immediate BD HSR was 4.7%, with a clinical presentation of anaphylaxis in 3.9% (tocilizumab [n = 3], rituximab [n = 2], positive skin test with culprit BD [n = 3]). Among patients with BD HSR, the median follow-up was longer (84.5 vs 54 months, P = .048), and renal (33.3% vs 4.1%, P = .002), hematologic involvement (16.7% vs 0, P < .001), and active disease (83.3% vs 13.9%, P < .001) were more common. Logistic regression analysis revealed that renal involvement, more than 14 hospitalizations per lifetime, and more than two different BD used were associated with BD hypersensitivity. CONCLUSION: The frequency of severe immediate HSR due to BD was shown to be 3.9% in children with rheumatic diseases. Children with active rheumatic disease and who have exposure to multiple BD should be monitored for BD HSR, particularly during intravenous BD infusions.

The factors affecting the disease course in Kawasaki disease.

The aim of this study was to review the characteristics of patients with Kawasaki disease (KD) from Turkey and to assess the performance of the Kobayashi score (KS), Harada score (HS), Formosa score (FS), Egami score (ES) and other parameters in predicting intravenous immunoglobulin (IVIG) resistance and coronary artery involvement (CAI) in the Turkish population. Patients who were diagnosed as being in the acute phase of KD at Hacettepe University Faculty of Medicine (Ankara, Turkey) between June 2007 and January 2016 reviewed retrospectively, and those between January 2016 and February 2018 reviewed prospectively, were included in this cohort study. A total of 100 patients with KD were included in this study. Statistical Package for Social Sciences for Windows 22.0 (SPSS Inc, Chicago, IL, USA) was used for statistical analysis. Eighty-five patients (85%) responded to IVIG treatment, whereas 15 (5 female, 10 male) were IVIG resistant. CAI was detected in echocardiography at diagnosis in 31 (31%) (9 female; 22 male) patients. For predicting IVIG resistance, KS, ES, FS, and HS had sensitivity of 82.1%, 26.7%, 30.8%, 69.2% and specificity of 35.7%, 94%, 51.2%, 45.8%, respectively. For the association with CAI occurrence, the sensitivities were 17.2%, 3.3%, 35.7%, 70.4% and the specificities were 78.5%, 88.4%, 49.3%, 49.3% for the aforementioned scores, respectively. The multivariate analysis showed white blood cell (WBC) count [Odd's ratio (OR) 4.1; 95% confidence interval (CI) 1.26-13.23; p = 0.019] and hematocrit (OR 3.8; 95% CI 1.15-12.4; p = 0.028), as independent predictors of CAI while gamma-glutamyl transferase (GGT) level (OR 5.7; 95% CI 1.73-27.51; p = 0.018) was detected as the only independent predictor of IVIG resistance. This is the first study from Turkey in KD to evaluate the association of the scoring systems for IVIG resistance and CAI. The risk scoring systems in KD did not predict the risk for IVIG resistance and were not associated with CAI in Turkish population.

Current State of Precision Medicine in Primary Systemic Vasculitides.

Precision medicine (PM) is an emerging data-driven health care approach that integrates phenotypic, genomic, epigenetic, and environmental factors unique to an individual. The goal of PM is to facilitate diagnosis, predict effective therapy, and avoid adverse reactions specific for each patient. The forefront of PM is in oncology; nonetheless, it is developing in other fields of medicine, including rheumatology. Recent studies on elucidating the genetic architecture of polygenic and monogenic rheumatological diseases have made PM possible by enabling physicians to customize medical treatment through the incorporation of clinical features and genetic data. For complex inflammatory disorders, the prevailing paradigm is that disease susceptibility is due to additive effects of common reduced-penetrance gene variants and environmental factors. Efforts have been made to calculate cumulative genetic risk score (GRS) and to relate specific susceptibility alleles for use of target therapies. The discovery of rare patients with single-gene high-penetrance mutations informed our understanding of pathways driving systemic inflammation. Here, we review the advances in practicing PM in patients with primary systemic vasculitides (PSVs). We summarize recent genetic studies and discuss current knowledge on the contribution of epigenetic factors and extracellular vesicles (EVs) in disease progression and treatment response. Implementation of PM in PSVs is a developing field that will require analysis of a large cohort of patients to validate data from genomics, transcriptomics, metabolomics, proteomics, and epigenomics studies for accurate disease profiling. This multi-omics approach to study disease pathogeneses should ultimately provide a powerful tool for stratification of patients to receive tailored optimal therapies and for monitoring their disease activity.

Is age associated with disease severity and compliance to treatment in children with familial Mediterranean fever?

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease in the world. The disease characteristics may vary in different age groups. In this study, we aimed to compare disease characteristics and treatment compliance according to the age of pediatric FMF patients. This is a single-center, cross-sectional study. Between August and October 2016, patients who were diagnosed with FMF, participated to the study. 378 pediatric FMF patients were enrolled in the study. Among those, age at symptom onset was ≤ 5 years in 69%, 6-11 years in 26% and ≥ 12 years in 5%. Patients older than 12 years old at symptom onset, had significantly less frequent fever attacks than the patients from other age groups. Patients younger than 5 years old at symptom onset had significantly higher international severity scoring system for FMF (ISSF) than other patients. And M694V homozygosity was significantly more frequent in patients with younger age at symptom onset. Patients younger than 5 years old were using their drugs more regularly than the other age groups (p = 0.002). Drug compliance was 90.5% in patients ≤ 5 years, 64.4% in patients 6-11 years, 58.3% in patients ≥ 12 years. The disease characteristics of FMF may differ between patients with different age at symptom onset. Younger age at disease onset seems to be related with more severe course; thus these patients should be followed-up more closely. In addition, treatment compliance which is critical for prevention of amyloidosis in FMF should be questioned especially in adolescent patients.

A new biopsychosocial and clinical questionnaire to assess juvenile idiopathic arthritis: JAB-Q.

OBJECTIVE: To create a new multidimensional questionnaire for the assessment of juvenile idiopathic arthritis (JIA) patients in standard clinical practice and study the validity and reliability of this questionnaire. METHODS: The Juvenile Arthritis Biopsychosocial and Clinical Questionnaire (JAB-Q) was created using the Delphi technique and consensus conference following an initial literature search. The questionnaire has three parts including a clinician form, child form and parent form. This is a patient/parent-centered outcome tool, which helps us to evaluate the biopsychosocial aspects of the patient, including disease activity, posture, functional and psychosocial status, fatigue, and performance in school. From January 2015 to January 2018, 6-18 years old children with JIA were enrolled in the study. The previously validated questionnaires were also applied to each participant to validate the JAB-Q: Juvenile Idiopathic Disease Arthritis Score (JADAS) and Childhood Health Assessment Questionnaire (CHAQ), and the Family Impact Questionnaire (FIS). The same questionnaire was re-administered after one week to assess the test-retest reliability in randomly selected 50 children and their parents. RESULTS: A group of experts were invited to the Delphi survey. After the Delphi tours, the final form of the questionnaire containing three parts as clinician form, child form and parent form was created. This tool was applied to 310 JIA patients and their parents. The children and parents easily handled the JAB-Q and filled the forms in around 10-15 min. The validity of the clinician, child and parents' forms were assessed by the JADAS, CHAQ, and FIS, respectively. The validity of these three scales were determined as moderate. In addition, the test-retest reliability of the clinician, child and parents' forms were considerably high. CONCLUSION: JAB-Q is a valid and reliable multidimensional biopsychosocial outcome tool that can be used routinely in clinical practice of pediatric rheumatology. The main advantage of this tool is incorporation of patients' and parents' perspectives separately while providing a practical and standard setting for the clinician's evaluation. However, further validation of this tool in an independent cohort is needed to improve its applicability.

Predictors of methotrexate response in Turkish children with oligoarticular and polyarticular juvenile idiopathic arthritis.

Batu ED, Sönmez HE, Gülhan B, Arici ZS, Topaloglu R, Bilginer Y. Predictors of methotrexate response in Turkish children with oligoarticular and polyarticular juvenile idiopathic arthritis. Turk J Pediatr 2017; 59: 6-12. Methotrexate (MTX) is the most commonly used disease modifying anti-rheumatic drug in juvenile idiopathic arthritis (JIA). We aimed to define predictor factors for response to MTX in Turkish children with oligo- and polyarticular JIA. We reviewed the medical files of 59 oligo- and 57 polyarticular JIA patients seen in the clinic between May 2008 and May 2013 and who received MTX for ≥6 months. MTX responders were defined as having no/low disease activity according to juvenile arthritis disease activity score 71 (JADAS71) at 6 months after MTX initiation. Median age at JIA diagnosis/MTX initiation was 70/78 months. Involvement of the small or upper extremity joints at disease diagnosis and MTX initiation was more frequent; antinuclear antibody (ANA) positivity was less frequent; acute phase reactants, JADAS71 at MTX initiation, and the frequency of polyarticular subtype were higher in MTX non-responders. In multiple logistic regression, oligoarticular JIA subtype and ANA positivity were independent predictors of MTX response.

Immunoglobulin G4-related orbital disease: report of two pediatric cases.

IgG4-related disease is a systemic fibro-inflammatory disorder mainly affecting the middle-aged and elderly population. IgG4-related orbital disease is very rare in childhood. We present here two children with IgG4-related orbital disease, one of whom responded well to prednisolone treatment while the other one was refractory to most immunosuppressive agents. It is important to treat patients at the early active stage of disease before fibrotic changes predominate. Thus, although rare, increased awareness of IgG4-related orbital disease in childhood may avoid delays in diagnosis and treatment.

Reviewing the recommendations for lupus in children.

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disorder with severe morbidity and mortality and diverse systemic involvement. Disease onset occurs during childhood in approximately 15 % of patients with SLE. It is important to treat the attacks adequately and prevent further flares for favorable long-term outcomes. The aim of effective disease management with early immunosuppression is to achieve symptomatic resolution and improvement in the quality of life by maintaining sustained remission and thereby preventing tissue damage. Adult literature on SLE management has evolved considerably over the past few decades based on observations from clinical studies investigating different immunosuppressive agents. We lack well-designed randomized controlled trials in children with SLE, thus we mainly depend on adult literature. Here, we review the literature for the current management of SLE in children and we present the recommendations and suggestions with the level of evidence.

Genetic epidemiological studies of congenital/prelingual deafness in Turkey: population structure and mating type are major determinants of mutation identification.

In order to evaluate the genetic epidemiology of deafness in Turkey, we first analyzed the pedigree data obtained from 2,169 families whose children were students of the schools for hearing loss/deafness in 31 cities of Turkey. Single major locus segregation analysis was performed after families were grouped according to hearing status of the parents. The results showed that sporadic phenocopies, autosomal dominant, and autosomal recessive transmission account for 18.2%, 4.9%, and 76.9% of the cases respectively, after exclusion of probands with unequivocal evidence for environmental etiologies. The high frequency of autosomal recessive transmission of this study differs from those of previous ones in Western populations. We subsequently analyzed the data from a subset of 574 unrelated families that were evaluated clinically, including mutation analysis of the GJB2 gene in 406 probands. Biallelic mutations were detected in 22.4% of all probands. They were present in 68.8% of probands whose parents were both deaf, yet in only 9.3% when both parents were hearing and consanguineous without a family history of deafness. Our study shows that GJB2 is the major gene for deafness in Turkey and was amplified in deaf by deaf matings, since assortative mating preferentially affects common genes. Deafness in the remaining families appears to result from mutations at many loci that are less frequent causes of deafness, because consanguinity has a proportionally greater effect on rare genes. Conclusions of this study may be relevant to other populations where consanguineous or assortative mating is present with various frequencies.