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.

Effect of comorbid benign joint hypermobility and juvenile fibromyalgia syndromes on pediatric functional gastrointestinal disorders.

OBJECTIVES: Musculoskeletal pain has a considerable frequency in pediatric outpatients. Benign joint hypermobility (BJHS) and juvenile fibromyalgia syndrome (JFMS) are non-inflammatory causes of musculoskeletal pain. In these syndromes, pain is often accompanied by various symptoms such as fatigue, sleep difficulties, mood disorders, cognitive dysfunction, dizziness, headaches, abdominal pain, irritable bowel syndrome, and restless legs syndrome. Functional dyspepsia, functional vomiting, functional abdominal pain, functional constipation, and irritable bowel syndrome all together are termed functional gastrointestinal (GI) disorders. We aimed to evaluate the functional gastrointestinal disorders association of BJHS and JFMS. METHODS: Patients aged 10-18 years who were diagnosed with functional GI disorder in the pediatric gastroenterology department were included in the study. The findings of BJHS and JFMS were evaluated by the pediatric rheumatology department. Scales for anxiety, somatization, and depression were administered by a child psychiatrist. COMPASS 31 scoring was used in autonomic dysfunction. RESULTS: The prevalence of JFMS and BJHS was 64% and 32%, respectively in children with a functional GI disorder. Retrosternal chest pain, dysphagia, early satiation, nausea, vomiting, and regurgitation were common in JFMS (p = 0.007; p = 0.005; p = 0.018; p = 0.002, p = 0.013; p = 0.014, respectively). Gastrointestinal symptoms did not differ with BJHS. One hundred six (88.3%) and 99 (82.5%) had orthostatic intolerance and reflex syncope, respectively. One hundred three (85.6%) had anxiety symptoms, 101 (84.2%) had somatization symptoms, and 102 (85%) had depression symptoms. CONCLUSIONS: Functional GI disorders, JFMS, and BJHS are complex intertwined disorders influenced by emotional distress. Therefore, a multidisciplinary approach is necessary for the diagnosis and treatment process.

Evaluation of liver elasticity with shear-wave elastography in juvenile idiopathic arthritis patients receiving methotrexate.

BACKGROUND: Methotrexate (MTX) is the first-choice disease-modifying drug in juvenile idiopathic arthritis (JIA) treatment. Methotrexate is metabolized in the liver and can cause liver toxicity and fibrosis with long-term use. Ultrasound shear wave elastography (SWE) is a non-invasive method and can detect liver fibrosis by evaluating the liver elasticity. The aim of this study was to assess liver stiffness and detect if there is an increase in liver stiffness or fibrosis findings with the non-invasive SWE method in JIA patients under MTX treatment. METHOD: The study included 49 JIA patients under MTX treatment and 48 healthy controls, matched for age and sex with a body mass index below the 95th percentile. The demographic data and clinical characteristics of patients were obtained from medical records. Liver function tests were evaluated, and liver tissue stiffness measurements were performed with SWE. RESULTS: Of the 49 patients, 67.35% were girls and the mean age was 10.69 (±4.33) years. The duration of MTX treatment was 23.00 (1-80) months, and the cumulative dose of MTX was 1,280.867 mg (±934.2) in the patient group. There was no statistically significant difference in liver stiffness between patients receiving MTX and healthy controls (P = 0.313). There was no relationship between MTX duration, cumulative dose, route of administration, and liver stiffness. Only gamma glutamyl transferase values were weakly correlated with liver stiffness (P = 0.029). CONCLUSIONS: We did not detect an increase in liver tissue stiffness in JIA patients using methotrexate in comparison with controls.

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.

Unexpected condition in a rare disease: encephalopathy in early-onset sarcoidosis.

BACKGROUND: Granulomatous autoinflammatory diseases are monogenic syndromes caused by mutations in the region encoding the nucleotide-binding domain of the nucleotide-binding oligomerization domain-containing 2 gene. Blau syndrome and early-onset sarcoidosis are familial and sporadic forms of the same disease and are very rare. Many organ systems may be involved; however, neurologic involvement is infrequent. We reported a case of encephalitis in a 12-year-old girl followed with a diagnosis of early-onset sarcoidosis. CASE: The patient was diagnosed with juvenile idiopathic arthritis at 3 years of age. We considered druginduced sarcoidosis at 6 years of age with granulomatous inflammation of liver and kidney. Small joint involvement and camptodactyly developed during follow-up. M315T mutation was detected in the NOD2 gene supporting the diagnosis of early-onset sarcoidosis. The patient suffered from encephalopathy when she was under methotrexate, infliximab, and systemic steroid treatment at 12 years of age. Cerebrospinal fluid limbic encephalitis antibody panel was negative. CONCLUSION: Encephalopathy is not common in Blau syndrome and early-onset sarcoidosis. The cause of encephalopathy in our patient was interpreted as autoimmune encephalitis.

Factors and glucocorticoid usage affecting the prognosis of systemic juvenile idiopathic arthritis.

BACKGROUND: The rate of glucocorticoid (GC) use is significantly higher in systemic juvenile idiopathic arthritis (SJIA) than other juvenile idiopathic arthritis subtypes. There is no consensus on the duration and dosage of GC treatment. We aimed to investigate the risk factors for a polyphasic / persistent disease course and the effect of dose and duration of GC treatment on SJIA prognosis. METHODS: Forty-two patients who were diagnosed with SJIA, and for whom the duration of disease was longer than 2 years, were included. Patients were divided into monophasic and others (polyphasic / persistent disease course). Risk factors for polyphasic / persistent disease course, which were clinical and laboratory findings regarding the patients, treatment options, dose, and duration of GCs, were evaluated for the first active disease periods and for all flares in the entire disease course. RESULTS: Of the 42 SJIA patients, 21 had monophasic, and 21 had polyphasic / persistent disease. Cumulative dosages and durations of glucocorticoid treatment were similar in the two groups at the first flare (odds ratio (OR): 1.032 P: 0.671; OR:1,113 P: 0.115). Durations of the first active disease period were longer in the polyphasic / persistent group (OR:1.275, P: 0.01). Active disease duration cut-off values of 1.5 months with sensitivity 85.7%, specificity 52.4% were observed on receiver operating characteristic curve analysis. The presence of hepatosplenomegaly at first flare was detected as an independent risk factor of polyphasic/persistent disease by multivariate analysis included both dosage and duration of a steroid (hazard ratio (HR): 4.129, P: 0.034), (HR: 3.992, P: 0.038). Multivariate recurrent events survival analysis determined ALT levels as a risk factor affecting polyphasic / persistent disease (HR: 0.986, P: 0.037). CONCLUSIONS: Glucocorticoid dose and duration did not affect the active disease periods and disease course in SJIA. An active disease period longer than 1.5 months, presentation of hepatosplenomegaly at the initial disease course, and high ALT levels at the recurrences should warn physicians of polyphasic / persistent disease.

Blau Syndrome and Early-Onset Sarcoidosis: A Six Case Series and Review of the Literature.

OBJECTIVES: This study aims to discuss the clinical, laboratory and genetic findings, and treatment options for six patients who were diagnosed with Blau syndrome (BS)/early-onset sarcoidosis (EOS). PATIENTS AND METHODS: The study included four patients (2 males,2 females; mean age 7 years; range 4 to 10 years) with EOS and two siblings (1 male, 1 female; mean age 10 years; range, 9 to 11 years) with BS. Age, age of initial symptoms, age of diagnosis; articular involvement, presence of uveitis, dermatitis, or fever, other organ involvement, laboratory findings, results of metabolic tests for mucopolysaccharidosis and mucolipidosis, results of genetic, pathologic, and immunologic tests, radiologic findings to evaluate skeletal dysplasia, and treatment options were collected. RESULTS: The median age at diagnosis of all patients was 6 years (range, 1 to 10 years). Five patients had camptodactyly and bilateral boggy synovitis in the wrists and ankles, one had granulomatous inflammatory changes in the liver and kidney biopsy, and one had attacks of fever and granulomatous dermatitis. None had uveitis. The detected mutations in nucleotide-binding oligomerization domain containing 2 (NOD2) were P268S (rs2066842), M513T (rs104895473), R702W (rs2066844), V955I (rs5743291), H343Y (rs199858111), and M491L (16:50745293). The treatments of patients included corticosteroids, non-steroid anti-inflammatory drugs, methotrexate, infliximab, adalimumab, anakinra, and canacinumab. CONCLUSION: Camptodactyly and boggy synovitis are important signs of BS/EOS. Methotrexate and tumor necrosis factor blockers are more effective in patients with predominantly articular symptoms. In patients 5 and 6 and their mother, we determined a novel M491L mutation in the NOD2 gene. Currently, this work is in progress towards identifying the pathogenesis and treatment options for this disease.

Patient Outcomes of Henoch-Schönlein Purpura Nephritis According to the New Semiquantitative Classification.

Background: A new semiquantitative classification (SQC) for pediatric Henoch-Schönlein nephritis (HSN) was defined recently. The outcomes of pediatric HSN patients are reevaluated according to the new classification. Methods: Primary kidney biopsies from 80 HSN patients were scored using the new SQC. The International Study of Kidney Disease in Children (ISKDC) and SQC classifications were compared in terms of the patient outcomes. Outcomes were defined as: Outcome A (n = 44) patients with no sign of renal disease, Outcome B (n = 32) patients with minor urinary abnormalities, and Outcome C (n = 4) patients with active renal disease. Results: The patients with outcome C had significantly higher biopsy scores and chronicity indices than patients in group A. There was no significant difference in areas under the curve between total biopsy SQC scores and ISKDC findings. Conclusions: Our results suggest that the modified SQC is not more sensitive than ISKDC classification for predicting the outcome in HSN cases.

Clinical and histopathological prognostic factors affecting the renal outcomes in childhood ANCA-associated vasculitis.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are very rare in childhood with an increased risk of morbidity and mortality. We aimed to evaluate renal prognostic factors in childhood AAV from the perspective of ANCA serotype, histopathological classification, and five-factor score (FFS). METHODS: Pediatric AAV patients from 11 referral centers in Turkey had been included to the study. The demographics, clinical findings, AAV subtypes, outcomes, and FFS were evaluated retrospectively. Kidney biopsies were classified histopathologically. RESULTS: Totally, 39 patients were enrolled in the study. Among all patients, 74.4% had renal involvement, 56.4% ear-throat-nose involvement, and 51.3% had musculoskeletal involvement. Proteinase 3 (PR3)-ANCA was positive in 48.7%, and myeloperoxidase (MPO)-ANCA was positive in 30.8%. 69.2% of patients had impaired renal function, and 28.2% had progressed to end-stage renal disease (ESRD) during the follow-up. At the time of diagnosis, FFS was ≥ 2 in 53.8%. The most common histopathologic classifications were as follows: crescentic type in 40.7% and sclerotic type in 25.9%. Gastrointestinal and renal involvement, MPO-ANCA positivity, serum creatinine levels, and impaired renal function during the follow-up were significantly higher in patients with FFS ≥ 2, compared to patients with FFS < 2. Patients with FFS ≥ 2 had more common crescentic, mixed and sclerotic histopathologic findings in biopsies. By logistic regression analysis forward method, the strongest single-risk factor among all the parameters was the initial level of creatinine in patients with ESRD, compared to the other patients (p = 0,007). CONCLUSIONS: Evaluation of the FFS, ANCA serology, and the creatinine levels may help to predict renal prognosis.

Epidermolysis bullosa complicated with nephrotic syndrome due to AA amyloidosis: A case report and brief review of literature.

Epidermolysis bullosa (EB) encompasses a clinically and genetically heterogeneous group of rare inherited diseases characterized by marked mechanical fragility of epithelial tissues with blistering and erosions following minor trauma. Amyloidosis is one of the most important complications of EB mostly seen in recessive dystrophic EB (RDEB) patients and can involve the kidney, bowel, liver, and also respiratory system. Herein, we present a child, who is probably the youngest case of genetically diagnosed RDEB, complicated with amyloidosis reported in literature. A 6-year-old boy who was diagnosed with EB was referred to our center with nephrotic-range proteinuria and hypoalbuminemia. He had homozygous mutation in COL7A1 gene. Kidney biopsy was remarkable for amyloidosis with positive Congo red staining, and amyloid fibrils were seen on electron microscopy. Although he did not have any symptoms of autoimmune diseases and mutation in the MEFV gene, he was given colchicine because of positive family history for familial Mediterranean fever and amyloidosis.

Adnexal masses in women with breast cancer.

BACKGROUND: Adnexal masses detected in breast cancer survivors are of particular concern because of the increased risk of ovarian malignancy. AIMS: This study was performed to analyse adnexal masses among women with breast cancer with regard to variables predictive of malignancy. METHODS: The study included women with breast cancer who had undergone surgery for an adnexal mass between 2002 and 2010 at Hacettepe University Hospital. A total of 45 consecutive women with a mean age of 47.3 years (range 25-76) were analysed retrospectively. RESULTS: Of 45 cases reviewed, benign ovarian pathology was found in 35 cases (77.8%) and malignant ovarian neoplasms were found in 10 cases (22.2%). A simple ovarian cyst was observed in 25 cases (71.4%) as the most common type of benign pathology. Of the 10 cases with malignancy, 5 (50%) had primary ovarian carcinoma, while the remaining five women had breast carcinoma metastases to the ovary. Complex mass at ultrasonography, increased CA 125 level and oestrogen receptor-negative tumour were found to be the significant predictors of ovarian malignancy. CONCLUSIONS: Although an adnexal mass in a woman with breast cancer is most commonly a benign ovarian cyst, the overall risk of ovarian malignancy is increased with breast cancer. An adnexal mass with complex architecture detected by ultrasonography and high CA 125 level were the strongest risk factors associated with increased risk of malignancy.

An unusual complication of uterine prolapse. Bilateral severe hydronephrosis.

Obstructive uropathy with bilateral hydronephrosis may be seen in uterine procidentia cases. Early recognition and treatment can prevent irreversible renal damage. Although this association has been known for a long time, it is clinically under evaluated most of the time. Here, we present a neglected case of total uterine procidentia in a 64-year-old woman who was detected also to have renal dysfunction. After surgical correction of procidentia, renal function tests returned to normal.