Insights into the clinical presentation of juvenile systemic lupus erythematosus: the PRAGMA monocentric cohort of 177 patients.

OBJECTIVES: The aim of this work is to describe the clinical manifestations at onset and during follow-up in a monocentric cohort of patients with juvenile systemic lupus erythematosus (jSLE) from the Paediatric Rheumatology group of the Milan area (PRAGMA). METHODS: Patients were retrospectively included in case of i) SLE diagnosis according to the 1997 American College of Rheumatology or the 2012 SLICC classification criteria and ii) disease onset before 18 years. RESULTS: Among the 177 recruited patients (155 females), haematologic involvement was the most common disease manifestation (75%), followed by joint and cutaneous involvements (70% and 57%, respectively). Renal disease was observed in 58 patients (32.8%), neurological complications in 26 cases (14.7%). Patients presented most commonly 3 clinical manifestations (32.8%), while 2 organ involvements were identified in 54 patients (30.5%) and 4 in 25 subjects (14.1%). The 49 patients with disease onset <10 years had less commonly articular involvement (p=0.02), while patients aged >14.8 years displayed less neurological manifestations (p=0.02). At a median follow-up of 118 month, the disease progressed in 93 patients, with a median of 2 new manifestations per patient. Low complement at diagnosis predicted new clinical manifestations (p=0.013 for C3 and p=0.0004 for C4). The median SLEDAI at diagnosis was 13; SLEDAI was substantially similar at 6 months, decreased at 12 months to remain stable at 18 months and further reduce at 24 months (p<0.0001). CONCLUSIONS: These data from a large jSLE monocentric cohort allow gaining further insights into a rare disease with a still high morbidity burden.

ASAH1 pathogenic variants associated with acid ceramidase deficiency: Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.

Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N-acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up-to-date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty-five patients representing the known clinical spectrum of Farber disease (living patients aged 1-28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease-causing variants.

Progressive pseudorheumatoid dysplasia: a rare childhood disease.

Progressive pseudorheumatoid dysplasia (PPRD) is a genetic bone disorder characterised by the progressive degeneration of articular cartilage that leads to pain, stiffness and joint enlargement. As PPRD is a rare disease, available literature is mainly represented by single case reports and only a few larger case series. Our aim is to review the literature concerning clinical, laboratory and radiological features of PPRD. PPRD is due to a mutation in Wnt1-inducible signalling protein 3 (WISP3) gene, which encodes a signalling factor involved in cartilage homeostasis. The disease onset in childhood and skeletal changes progresses over time leading to significant disability. PPRD is a rare condition that should be suspected if a child develops symmetrical polyarticular involvement without systemic inflammation, knobbly interphalangeal joints of the hands, and gait abnormalities. A full skeletal survey, or at least a lateral radiograph of the spine, can direct towards a correct diagnosis that can be confirmed molecularly. More than 70 WISP3 mutations have so far been reported. Genetic testing should start with the study of genomic DNA extracted from blood leucocytes, but intronic mutations in WISP3 causing splicing aberrations can only be detected by analysing WISP3 mRNA, which can be extracted from cultured skin fibroblasts. A skin biopsy is, therefore, indicated in patients with typical PPRD findings and negative mutation screening of genomic DNA.

Disease status, reasons for discontinuation and adverse events in 1038 Italian children with juvenile idiopathic arthritis treated with etanercept.

BACKGROUND: Data from routine clinical practice are needed to further define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). The aim of this analysis was to investigate the disease status, reasons for discontinuation and adverse events in Italian JIA patients treated with etanercept (ETN). METHODS: In 2013, all centers of the Italian Pediatric Rheumatology Study Group were asked to make a census of patients given ETN after January 2000. Patients were classified in three groups: group 1 = patients still taking ETN; group 2 = patients discontinued from ETN for any reasons; group 3 = patients lost to follow-up while receiving ETN. All three groups received a retrospective assessment; patients in group 1 also underwent a cross-sectional assessment. RESULTS: 1038 patients were enrolled by 23 centers: 422 (40.7%) were in group 1, 462 (44.5%) in group 2, and 154 (14.8%) in group 3. Median duration of ETN therapy was 2.5 years. At cross-sectional assessment, 41.8% to 48.6% of patients in group 1 met formal criteria for inactive disease, whereas 52.4% of patients in group 2 and 55.8% of patients in group 3 were judged in clinical remission by their caring physician at last visit. A relatively greater proportion of patients with systemic arthritis were discontinued or lost to follow-up. Parent evaluations at cross-sectional visit in group 1 showed that 52.4% of patients had normal physical function, very few had impairment in quality of life, 51.2% had no pain, 76% had no morning stiffness, and 82.7% of parents were satisfied with their child's illness outcome. Clinically significant adverse events were reported for 27.8% of patients and ETN was discontinued for side effects in 9.5%. The most common adverse events were new onset or recurrent uveitis (10.2%), infections (6.6%), injection site reactions (4.4%), and neuropsychiatric (3.1%), gastrointestinal (2.4%), and hematological disorders (2.1%). Ten patients developed an inflammatory bowel disease and 2 had a malignancy. One patient died of a fulminant streptococcal sepsis. CONCLUSIONS: Around half of the patients achieved complete disease quiescence under treatment with ETN. The medication was overall well tolerated, as only one quarter of patients experienced clinically significant adverse events and less than 10% had treatment discontinued for toxicity.

Nervous system involvement in Farber disease.

A 30 months-old boy with Farber disease developed nystagmus 12 months after hematopoietic stem cell transplantation (HSCT). At 40 months, gait ataxia was evident, and brain MRI showed increased size of pericerebellar sulci and 4th ventricle. EMG showed denervation in the tongue and upper limb muscles, consistent with motor neuron disease. HSCT improves the peripheral manifestations of Farber disease, but may not prevent the progressive neurological deterioration.

May biscuits contribute to iron balance? An observation in children with juvenile idiopatic arthritis.

Within an observational open study on the effects of a scheduled dosage of biscuits with iron, children with juvenile idiopathic arthritis were either supplemented with biscuits supplying iron fumarate (median 3.6 mg per day) or left to their customary dietary habits. After 4 months, supplemented children showed a more favourable percentage change of blood haemoglobin, while ferritin levels (markers of inflammation) remained stable. We conclude that the supply of iron with available dietary products may contribute to an adequate iron status in children with chronic inflammatory disorders in a stable situation.

Immunogenicity, safety and tolerability of a bivalent human papillomavirus vaccine in adolescents with juvenile idiopathic arthritis.

AIMS: To evaluate the immunogenicity, safety and tolerability of the bivalent HPV vaccine in female patients with juvenile idiopathic arthritis (JIA). METHODS: Twenty-one patients with JIA aged 12-25 years and 21 healthy controls were enrolled and received three doses of the bivalent HPV vaccine. RESULTS: All of the subjects were seronegative at baseline and seroconverted after the scheduled doses. The JIA patients showed significantly lower HPV16 neutralising antibody titres than controls 1 month after the administration of the third dose (p < 0.05), whereas no significant difference was observed in HPV18 neutralising antibody titres. Local and systemic reactions were similarly frequent in the patients and controls, and there were no significant changes in 27-joint juvenile arthritis disease activity score or laboratory tests. CONCLUSION: The bivalent HPV vaccine is safe in patients with stable JIA and regardless of the use of medications the vaccine assures an adequate degree of protection for a certain time.

Chorea, a little-known manifestation in systemic lupus erythematosus: short literature review and four case reports.

Chorea is a movement disorder that may be found in children due to several causes. Here we focus especially on Systemic Lupus Erythematosus associated chorea. First we outline its epidemiology, hypothesized pathogenesis, clinical presentation and treatment, then we report four significant clinical cases, which represent well the extreme variability of set of symptoms that may accompany lupus chorea. Our experience, according to literature, suggests that choreic movements in a child should alert the pediatrician and lead him to investigate a potential neurological involvement of Systemic Lupus Erythematosus.