Evolution of echocardiographic and cardiac magnetic resonance imaging abnormalities during follow-up in patients with multisystem inflammatory syndrome in children.

AIMS: Multisystem inflammatory syndrome in children (MIS-C) with cardiovascular manifestations are frequent. However, there is lacking evidence regarding cardiological follow-up of this cohort of patients. The aim of our study was to describe the early and mid-term cardiac abnormalities assessed by standard and speckle-tracking echocardiography (STE), and cardiac MRI (CMR). METHODS AND RESULTS: We enrolled 32 patients (21 male, 11 female), mean age 8.25 ± 4years, with diagnosis of MIS-C. During admission, all children underwent TTE, STE with analysis of left ventricle global longitudinal strain (GLS) and CMR. Patients underwent cardiological evaluation at 2 (T1) and 6 months (T2) after discharge. Cardiac MRI was repeated at 6 months after discharge. Mean left ventricular ejection fraction (LVEF) at baseline was 58.8 ± 10% with 10 patients (31%) below 55%. Speckle-tracking echocardiography showed reduced mean LV GLS (-17.4 ± 4%). On CMR, late gadolinium enhancement (LGE) with non-ischaemic pattern was evident in 8 of 23 patients (35%). Follow-up data showed rapid improvement of LVEF at T1 (62.5 ± 7.5 vs. 58.8 ± 10.6%, P-value 0.044) with only three patients (10%) below ≤ 55% at T1. Left ventricular (LV) GLS remained impaired at T1 (-17.2 ± 2.7 vs.-17.4 ± 4, P-value 0.71) and significantly improved at T2 (-19 ± 2.6% vs. -17.4 ± 4%, P-value 0.009). LV GLS was impaired (>-18%) in 53% of patients at baseline and T1, whereas only 13% showed persistent LV GLS reduction at T2. Follow-up CMR showed LGE persistence in 33.4% of cases. CONCLUSION: Early cardiac involvement significantly improves during follow-up of MIS-C patients. However, subclinical myocardial dysfunction seems to be still detectable after 6 months of follow-up in a not negligible proportion of them.

Cone beam computed tomography for the assessment of linear scleroderma of the face.

BACKGROUND: To date, standardized methods for assessing the disease progression of linear scleroderma of the face (LSF) are lacking. OBJECTIVES: We investigated whether Cone Beam Computed Tomography (CBCT) may represent a reliable tool for assessing linear scleroderma of the face (LSF). METHODS: Ten patients with LSF and five age-matched controls underwent CBCT assessment. The transverse sections at three anatomic levels of the maxillofacial bones were analyzed. Measurements of soft tissue and total thickness of both affected and unaffected side of the face were made by a standardized methodology. Six raters evaluated CBCTs twice and blindly one from the other. The intra- and inter-rater reliability was assessed by the Intraclass Correlation Coefficient (ICC). RESULTS: CBCT was fast and well tolerated by the patients. The inter-rater concordance for the total thickness was excellent, mean ICC 0.75 for patients, 0.89 for controls. The mean ICC for soft tissue thickness was 0.49 for patients, 0.66 for controls. 58.3% of the measurements for patients and 91.2% of those for controls showed excellent ICC results (≥ 0.75). The intra-rater concordance resulted optimal (ICC 0.77-0.99). CONCLUSIONS: CBCT is a reliable technique to assess skin and bony changes of LSF.

Psychological profile in children and adolescents with severe course Juvenile Idiopathic Arthritis.

OBJECTIVE: Juvenile Idiopathic Arthritis (JIA) is the most common chronic pediatric rheumatic disease. It is recognized that only reliance on clinical signs of disease outcome is inadequate for understanding the impact of illness and its treatment on child's life and functioning. There is a need for a multidisciplinary and holistic approach to children with arthritis which considers both physical and emotional functioning. This study investigated the psychosocial functioning of children and adolescent with JIA and the disease-related changes in their family. METHODS: The sample consisted of 33 hospitalized patients, aged 6-16 years. Both parents and the children were given a number of questionnaire to fill out. Clinical information was extracted from the interviews. RESULTS: Self-reported psychological functioning (depression, anxiety, and behavior) was not different from the normal population; however significant psychological suffering was detected by the clinical interview. CONCLUSIONS: Children and adolescents with JIA do not show overt psychopathology by structured assessment; nevertheless a more clinically oriented holistic approach confirms JIA as a disrupting event causing relevant changes in the quality of life of the affected families.

Complementary and Alternative Medicine (CAM) in paediatric rheumatology: a European perspective.

OBJECTIVES: To analyse the use of complementary and alternative medicine (CAM) in children with rheumatic diseases, treated at a paediatric rheumatology centre in Italy. METHODS: Parents of children with different kinds of chronic rheumatic diseases anonymously completed a questionnaire about their children's past or current use of CAM. Two groups of patients were analysed: Group A consisted of children who were still attending the centre; Group B consisted of children who had not attended the clinic for more than one year. RESULTS: 150 completed surveys were analysed: 22 paediatric patients (14.7%), 10/100 in group A and 12/50 in group B, used CAM to treat their diseases. The therapies used the most were homeopathy, herbal remedies, vitamins and minerals. We observed a significantly greater use of CAM among patients who had not attended the clinic for more than one year (24%) as compared to those who were regularly checked (10%) (p=0.02). Parents' use of CAM was significantly related to its use for their children (p=0.001). A poor outcome, probably related to the exclusive use of alternative treatments, was observed in three out of six patients who had completely stopped using traditional immunosuppressive drugs. CONCLUSIONS: Physicians should be aware of the use of CAM particularly in patients who skip their regular check-ups. The use of CAM to treat childhood rheumatic conditions in Italy seems to be less frequent than in North America.

Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene.

OBJECTIVE: To analyze the long-term impact of the R92Q mutation of TNFRSF1A in children with periodic fever, in comparison with children with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) with TNFRSF1A structural mutations and children with periodic fever of unknown origin fulfilling the criteria for periodic fever, aphthosis, pharyngitis, and adenitis syndrome (PFAPA). METHODS: The extracellular region of TNFRSF1A was analyzed in 720 consecutive children with periodic fever, using denaturing high-performance liquid chromatography and DNA sequencing. Followup data on 11 pediatric patients with TNFRSF1A structural mutations (cysteine or T50M), 23 pediatric patients with an R92Q substitution, and 64 pediatric patients with PFAPA were collected during routine clinic visits. The 50-item Child Health Questionnaire was used to assess health-related quality of life (HRQOL). RESULTS: The frequency of typical TRAPS-related clinical manifestations was significantly lower and the impact of the disease on HRQOL was significantly reduced in patients with the R92Q mutation compared with TRAPS patients carrying structural mutations of TNFRSF1A. Followup data on 11 TRAPS patients with TNFRSF1A structural mutations (mean followup 7.9 years), 16 patients with theR92Q substitution (mean followup 7.3 years), and 64 patients with PFAPA (mean followup 5.2 years) were available. Patients with R92Q mutations and patients with PFAPA displayed a higher rate of self-resolution or amelioration of the fever episodes than did TRAPS patients with structural mutations. CONCLUSION: Although some cases may progress to a more chronic disease course, the majority of children with an R92Q mutation of the TNFRSFA1 gene show a milder disease course than that in children with TNFRSFA1 structural mutations and have a high rate of spontaneous resolution and amelioration of the recurrent fever episodes.

Severe epilepsy preceding by four months the onset of scleroderma en coup de sabre.

Juvenile localized scleroderma (JLS) includes several subtypes including plaque morphea, linear scleroderma and the en coup de sabre type which affects face and head. The latter variety may involve the eye and the brain with various appearance and clinical complications.We describe the case of a 6-year-old boy who presented partial complex seizures, with status epilepticus, four months before the appearance of sclerodermatous skin lesions on the face. This case report raises important questions on the pathogenesis of JLS and, particularly, on the issue whether it is a mere autoimmune condition or a neuro-cutaneous disease.

The Italian version of the PedsQL in children with rheumatic diseases.

OBJECTIVE: The aim of the study was to test the reliability and validity of the Italian translation of the PedsQL 4.0 Generic Core Scales and the PedsQL 3.0 Rheumatologic Module in a sample of rheumatologic children in Italy. METHODS: The PedsQL 4.0 and the PedsQL 3.0 were administered to rheumatic and healthy children. 102 children 5-18 years old and 132 parents of children 2-18 years old were tested. Additionally, the Child Health Questionnaire - Parent Form 50 - was administered to the rheumatologic sample. RESULTS: Internal consistency reliability for group comparisons reached the recommended coefficient alpha of 0.70 for PedsQL 4.0 and PedsQL 3.0. The inter-correlation between these last ones was highly significant. The correlation between the PedsQL 4.0 and the CHQ was statistically significant. CONCLUSION: The Italian version of the PedsQL 4.0 and PedsQL 3.0 Rheumatology Module demonstrate acceptable reliability and validity for both patient self-report and parent proxy-report.

EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR).

PURPOSE: The optimal treatment of systemic sclerosis (SSc) is a challenge because the pathogenesis of SSc is unclear and it is an uncommon and clinically heterogeneous disease affecting multiple organ systems. The aim of the European League Against Rheumatism (EULAR) Scleroderma Trials and Research group (EUSTAR) was to develop evidence-based, consensus-derived recommendations for the treatment of SSc. METHODS: To obtain and maintain a high level of intrinsic quality and comparability of this approach, EULAR standard operating procedures were followed. The task force comprised 18 SSc experts from Europe, the USA and Japan, two SSc patients and three fellows for literature research. The preliminary set of research questions concerning SSc treatment was provided by 74 EUSTAR centres. RESULTS: Based on discussion of the clinical research evidence from published literature, and combining this with current expert opinion and clinical experience, 14 recommendations for the treatment of SSc were formulated. The final set includes the following recommendations: three on SSc-related digital vasculopathy (Raynaud's phenomenon and ulcers); four on SSc-related pulmonary arterial hypertension; three on SSc-related gastrointestinal involvement; two on scleroderma renal crisis; one on SSc-related interstitial lung disease and one on skin involvement. Experts also formulated several questions for a future research agenda. CONCLUSIONS: Evidence-based, consensus-derived recommendations are useful for rheumatologists to help guide treatment for patients with SSc. These recommendations may also help to define directions for future clinical research in SSc.

Mycophenolate mofetil for the treatment of juvenile onset SLE: a multicenter study.

Mycophenolate mofetil (MMF) has proved to be an efficacious and safe therapy in adult lupus nephritis. Recently, this drug has been suggested as a possible new alternative treatment also for juvenile-onset SLE (juvenile-SLE). A multicenter study has been performed to evaluate the efficacy and safety of MMF in controlling the disease activity in children and adolescents with juvenile-SLE. Our results show that MMF was effective in reducing the disease activity or as a steroid-sparing agent in 14 of 26 patients (54%), stabilised the disease in 8 (31%) and was ineffective in 4 (15%). In particular, in patients without renal involvement, a good response was registered in 9 of 13 patients (69%). Among those patients with renal involvement, MMF was effective in 5 of 13 patients (38%), partially effective in 4 (31%) and ineffective in 4 (31%). No severe side effects have been observed; only two patients stopped the drug because of severe diarrhoea and abdominal pain. With the limits of a retrospective study, MMF seems to be effective and safe for the treatment of juvenile-SLE, especially in patients with no renal involvement.

European League Against Rheumatism (EULAR) Scleroderma Trial and Research group (EUSTAR) recommendations for the treatment of systemic sclerosis: methods of elaboration and results of systematic literature research.

OBJECTIVE: To describe methods and procedures used for the development of the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trial and Research group (EUSTAR) recommendations for the treatment of systemic sclerosis. In particular, the results of a web-based Delphi exercise aimed at selection of research questions and evidence from systematic literature research, as parts of the development of these recommendations, are presented in detail. METHODS: In agreement with the EULAR standard operating procedures a Task Force was created that consisted of the EUSTAR board members, 10 systemic sclerosis (SSc) experts invited from outside the EUSTAR board and representing Europe, the USA and Japan, a clinical epidemiologist, 2 patients with SSc and 3 fellows for literature research. All EUSTAR centres were invited to contribute to the development of recommendations through submission and preliminary selection of the research questions. The systematic literature research was performed using the Pubmed, Medline, EMBASE and Cochrane databases. Retrieved trials were evaluated according to the Jadad classification, and the level of evidence was graded from 1 to 4. Outcome data for efficacy and adverse events were abstracted and effect size, number needed to treat (NNT) and number needed to harm (NNH) were calculated when appropriate. RESULTS: In all, 65 EUSTAR Centres provided 304 research questions concerning SSc treatment. These questions were aggregated, subdivided into 19 treatment categories and then subjected to preliminary selection by a web-based Delphi technique. The final set of 26 research questions was created by the Expert Committee based on the results of the Delphi exercise and the expert's experience. CONCLUSIONS: This paper is a comprehensive summary of the methods we used to build recommendations for the drug treatment of systemic sclerosis, combining an evidence based approach and expert opinion.

Factors affecting survival in juvenile systemic sclerosis.

OBJECTIVES: To determine whether demographic, clinical and immunological features may predict the outcome in juvenile SSc (JSSc). METHODS: Clinical and laboratory characteristics of patients with JSSc collected from paediatric rheumatology centres worldwide were analysed. First, univariate tests identified those features significantly related with fatal outcome, and then multivariate logistic regression analysis was applied to determine the predictors of mortality. RESULTS: One hundred and thirty-four patients from 40 centres were eligible for the analysis. Sixteen patients died and a rapidly fatal course was observed in most of them: 4/16 died within 1 yr after diagnosis and 10/16 within 5 yrs. At the moment of diagnosis, patients with poor outcome showed a significantly higher frequency of internal organ involvement, particularly cardiac, respiratory and gastrointestinal systems. No significant difference emerged for entity of skin, vascular and musculo-skeletal involvement, nor for auto-antibodies profile and laboratory tests. Multivariate analysis showed the following factors to be significant predictors of mortality: fibrosis on chest X-rays [odds ratio (OR) 11.2], raised creatinine levels (OR 22.7) and pericarditis (OR 41.3), while a short disease duration at diagnosis conferred protection (OR 0.3). CONCLUSIONS: All patients with JSSc and fatal outcome were affected by the diffuse form of the disease, and most of them showed a very rapid progression and early signs of internal organ involvement. This suggests that, in children, SSc may have two possible courses: a rapid development of internal organ failure leading to severe disability and eventually to death, or a slow course of the disease with lower mortality.

Iloprost treatment for refractory Raynaud's phenomenon in two infants.

Raynaud's phenomenon (RP) is rare in young children. We describe two infants with severe RP, manifesting as fingertip necrosis, who were resistant to conventional vasodilators and were treated successfully with iloprost, a prostacyclin analogue. The application of iloprost is safe and should be considered in children with threatening ischemic digits.

Preliminary evidence that etanercept may reduce radiographic progression in juvenile idiopathic arthritis.

OBJECTIVE: To investigate the rate of radiographic progression, as measured with the carpo-metacarpal ratio (Poznanski score), during etanercept (ETN) therapy in children with polyarticular juvenile idiopathic arthritis (JIA). METHODS: Patients included in the Italian ETN registry who had a standard radiograph of both hands and wrists in the posteroanterior view made at start of treatment and after 1 year were included in the study. The clinical response was assessed by means of the ACR Pediatric definition of improvement. Radiographic progression was determined by calculating the change in the Poznanski score between the baseline and the 1-year radiographs. RESULTS: A total of 40 patients were studied. The frequency of ACR pediatric 30, 50, and 70 response at 1 year was 77%, 72%, and 50%, respectively. The median change in the Poznanski score between baseline and 1 year was + 0.3 units, meaning that, on average, patients experienced improvement in radiographic progression. CONCLUSION: Our pilot study provides evidence that ETN is potentially capable of reducing the progression of radiographic joint damage in JIA. This finding deserves confirmation in a controlled trial.

Severe clinical course of systemic lupus erythematosus in the first year of life.

Systemic lupus erythematosus (SLE) very rarely occurs before the age of 5. Herein we describe the clinical features of infantile SLE (iSLE) with onset during the first year of life. The clinical and laboratory characteristics of iSLE patients followed at the Department of Pediatrics of Padua were analyzed. They were combined with those collected from the literature by performing a systematic literature search on PubMed using the following keywords: SLE, infant, laboratory, therapy, and outcome. A total of 13 patients with iSLE, 2 from our Institution and 11 from the literature, are included in this review. Seven (53.8%) were females and 6 were males (46.2%). The age at disease onset ranged from 6 weeks to 11 months. In comparison with juvenile systemic lupus erythematosus (jSLE), iSLE showed a higher prevalence of positive family history for autoimmune diseases, systemic symptoms at presentation, internal organs involvement, and shorter time between symptoms onset and diagnosis. Anemia and thrombocytopenia were present in the majority of the patients at diagnosis, whereas leukopenia was rarely observed. The overall prognosis in iSLE was very poor: 5/13 infants died between 2 and 31 months after the onset, and 5/13 had severe disease course with residual organ damage. SLE can start as early as during the first year of life and is more severe than in the later age groups.

Loss of efficacy during long-term infliximab therapy for sight-threatening childhood uveitis.

OBJECTIVE: To describe efficacy and safety of infliximab in the treatment of childhood chronic uveitis during a long-term follow-up. METHODS: Fifteen patients (median age 12 yrs, range 5-21 yrs) with chronic uveitis were enrolled. Before infliximab treatment, children had presented active uveitis despite treatment with MTX and/or CSA. All were also receiving oral prednisone (1-2 mg/kg/day) for at least 1 month. Infliximab (5 mg/kg) was administered at weeks 0, 2, 6 and then every 6-8 weeks. Later on, in patients enrolled in Florence the administration interval was progressively increased up to 10 weeks if uveitis did not flare, whilst in children from Padua the scheduled infusion rate was maintained every 6 weeks. Absence or recurrence rate of uveitis up to the last visit was recorded. RESULTS: Median follow-up on treatment was 30 months (range 16-38 months), median number of infusions 22 (range 11-30). During the first year, 13/15 children achieved a complete remission over a median period of 10 weeks, but all relapsed thereafter. The probability of a first relapse was correlated to length of treatment, once remission was achieved (P < 0.03). The total number of relapses correlated with the duration of treatment (r(s) = 0.81; P < 0.002) and with the total number of infusions (r(s) = 0.83; P < 0.001). The total number of relapses on treatment at last follow-up was not significantly different between the two centres. CONCLUSIONS: Even if limited to a small group, infliximab appears to be an effective treatment for uveitis in children, but its efficacy seems to wane over time.

A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children.

OBJECTIVE: To identify a set of clinical parameters that can predict the probability of carrying mutations in one of the genes associated with hereditary autoinflammatory syndromes. METHODS: A total of 228 consecutive patients with a clinical history of periodic fever were screened for mutations in the MVK, TNFRSF1A, and MEFV genes, and detailed clinical information was collected. A diagnostic score was formulated based on univariate and multivariate analyses in genetically positive and negative patients (training set). The diagnostic score was validated in an independent set of 77 patients (validation set). RESULTS: Young age at onset (odds ratio [OR] 0.94, P = 0.003), positive family history of periodic fever (OR 4.1, P = 0.039), thoracic pain (OR 4.6, P = 0.05), abdominal pain (OR 33.1, P < 0.001), diarrhea (OR 3.3, P = 0.028), and oral aphthosis (OR 0.2, P = 0.007) were found to be independently correlated with a positive genetic test result. These variables were combined in a linear score whose ability to predict a positive result on genetic testing was validated in an independent data set. In this latter set, the diagnostic score revealed high sensitivity (82%) and specificity (72%) for discriminating patients who were genetically positive from those who were negative. In patients with a high probability of having a positive result on genetic testing, a regression tree analysis provided the most reasonable order in which the genes should be screened. CONCLUSION: The proposed approach in patients with periodic fever will increase the probability of obtaining positive results on genetic testing, with good specificity and sensitivity. Our results further help to optimize the molecular analysis by suggesting the order in which the genes should be screened.

Esophageal involvement in juvenile localized scleroderma: a pilot study.

OBJECTIVES: To evaluate the esophageal involvement in patients with juvenile localized scleroderma (JLS). METHODS: A cohort of patients with JLS underwent esophageal stationary manometry to evaluate esophageal motility and lower esophageal sphincter (LES) function, distal esophagus 24-hour pH-monitoring to detect gastroesophageal reflux (GER) and upper gastrointestinal (GI) endoscopy to evaluate the presence of esophagitis. RESULTS: Fourteen patients (10 female, mean age 13.3 yrs, mean disease duration 4.7 yrs), took part in the study. Ten had linear scleroderma, three deep morphea, and one generalized morphea. Esophageal abnormalities were found in 8/14 patients (57%): pathological acid exposure on 24-hour pH-monitoring was found in 7; non-specific esophageal motor abnormalities in 5 and endoscopy-proved esophagitis in 5 symptomatic patients. Interestingly, 5 out of 8 patients with esophageal abnormalities were found to be ANA positive, and 2 were also RF positive. CONCLUSION: Esophageal involvement is not unusual in patients with juvenile localized scleroderma, even in the absence of specific symptoms. These preliminary findings, if confirmed in a larger cohort of patients, may support the indication for an extensive GI evaluation especially in presence of positive autoantibodies or specific GI symptoms.

Distinctive clinical features of pediatric systemic lupus erythematosus in three different age classes.

It is estimated that around 20% of patients with systemic lupus erythematosus (SLE) have their onset in childhood but there have been conflicting data about the prevalence and severity of the clinical features in different age classes. We conducted this study to analyse the clinical features of patients with pediatric SLE (pSLE) with onset in infancy, prepubertal and postpubertal age. The charts of patients followed at the Department of Pediatrics, University of Padua, who met the criteria for SLE diagnosis, were reviewed. Patients were divided into three groups based on age at disease onset: group A, patients < or =2 years old, group B patients aged between 2 and 10 years, group C patients between 11 and 16 years of age. The clinical and laboratory characteristics of each group were compared. Forty-two patients with pSLE entered the study: 2 were diagnosed before the age of 2 years, 11 between 2 and 10 years and 29 between 10 and 16 years. Eleven more patients with infantile (onset <2 years) SLE (iSLE) were found by a systematic literature search on PubMed and EmBASE and added for analysis to the group A. The female preponderance was significant only in postpubertal patients (F:M = 6.3: 1) whereas the other two groups presented a similar F:M ratio (1.2: 1). In comparison with the other two groups, iSLE showed a significantly higher prevalence of cardiovascular and pulmonary involvement, anemia and thrombocytopenia and a shorter disease duration at time of diagnosis. The postpubertal group showed a higher frequency of musculoskeletal involvement and leukopenia. In prepubertal patients there was no female preponderance and the frequency of clinical features was intermediate between infantile and postpubertal patients. Complement fractions level, antinuclear antibodies (ANA), anti-dsDNA, anti-cardiolipin antibodies and lupus anti-coagulant autoantibodies were not significantly different in the three groups. In general, the prevalence of internal organs involvement in pSLE seems to decrease with age. In infants, SLE is more severe than in the following ages. Postpubertal patients have a strong female preponderance and more specific signs of disease at onset. Prepubertal patients have an intermediate disease severity and no gender predilection.