Systemic sclerosis sine scleroderma in children is more aggressive than in adults.

OBJECTIVES: To compare the clinical and laboratory features of pediatric systemic sclerosis sine scleroderma (ssJSSc) with adult-onset ssSSc. METHODS: Demographic, clinical and laboratory data of ssJSSc, retrospectively retrieved from our hospital medical records, case reports from the literature and from the PRES JSSc registry, were compared with the Padua cohort of adult patients with ssSSc. Patients were defined as having ssSSc if they never had skin involvement but all the following features: (I) Raynaud's Phenomenon (RP) and/or digital vasculopathy, (II) positive antinuclear antibodies (ANA), (III) internal organs involvement typical of scleroderma, (IV) no other defined connective tissue diseases. RESULTS: Eighteen juvenile and 38 adult-onset ssSSc patients, mean disease duration 5.8 and 9.7 years, respectively, entered the study. The frequency of females affected was significantly lower in ssJSSc (38.9% vs 89.5%, p < 0.0001). When compared to adults, ssJSSc displayed less SSc-specific capillaroscopy abnormalities (68.8% vs 94.7%, p = 0.02) while significantly higher vascular (digital pitting scars, ulcers 35.3% vs 10.5%, p = 0.042), respiratory (50.0% vs 23.7%, p = 0.02) and cardiac involvement (50.0% vs 2.6%, p < 0.0001). The outcome was significantly worse in ssJSSc as six patients (33%) died (n = 3) or reached an end-stage organ failure (n = 3) in comparison to only two deaths (5.3%) in the adult cohort. Anti-centromere antibodies were significantly lower in children (20.0% vs 68.4%, p = 0.001) while no difference was noted for other SSc-specific autoantibodies. CONCLUSION: Compared to adults where ssSSc generally has an indolent course, children present with aggressive disease that heralds a worse prognosis characterized by high cardiorespiratory morbidity and mortality.Key Indexing Terms: scleroderma, juvenile systemic sclerosis, outcome, heart, pulmonary arterial.

Long non-coding RNA H19X as a regulator of mononuclear cell adhesion to the endothelium in systemic sclerosis.

OBJECTIVE: To define the functional relevance of H19 X-linked co-expressed lncRNA (H19X) in endothelial cell (EC) activation as a key process in systemic sclerosis (SSc) vasculopathy. METHODS: H19X expression in SSc skin biopsies was analyzed from single cell RNA sequencing (scRNA-seq) data. Differential expression and pathway enrichment analysis between cells expressing (H19Xpos) and non expressing H19X (H19Xneg) cells was performed. H19X function was investigated in human dermal microvascular EC (HDMECs) by silencing. H19X and EC adhesion molecules levels were analyzed by RT-qPCR and Western Blot after stimulation with proinflammatory cytokines. Cytoskeletal rearrangements were analyzed by fluorescent staining. Endothelial adhesion was evaluated by co-culture of HDMECs and fluorescent labelled peripheral blood mononuclear cells (PBMCs). Shedding VCAM1 was evaluated by ELISA on HDMEC supernatant. RESULTS: scRNA-seq showed significant upregulation of H19X in SSc compared with healthy EC. In HDMEC, H19X was consistently induced by type I and II interferons. H19X knockdown lead to a significant decrease of the mRNA of several adhesion molecules. Particularly, vascular cell adhesion protein 1 (VCAM1) was significantly reduced at protein and mRNA levels. Co-expression analysis of the scRNA-seq data confirmed a higher expression of VCAM1 in (H19Xpos) EC. EC were also strongly associated with the 'cell adhesion molecule' pathway. Moreover, VCAM1 downstream pathway displayed less activation following H19X knockdown. Contractility of HDMEC, PBMC adhesion to HDMEC and VCAM1 shedding were also reduced following H19X knockdown. CONCLUSIONS: lncRNA H19X may contribute to EC activation in SSc vasculopathy, acting as a regulator of expression of adhesion molecules in EC.

Non-invasive imaging and clinical skin scores in juvenile localised scleroderma.

OBJECTIVES: To evaluate whether in juvenile localised scleroderma (JLS), non-invasive imaging can differentiate affected from non-affected skin and whether imaging correlates with a validated skin score (Localised Scleroderma Cutaneous Assessment Tool, LoSCAT). METHODS: 25 children with JLS were recruited into a prospective study and a single 'target' lesion selected. High frequency ultrasound (HFUS, measuring skin thickness), infrared thermography (IRT, skin temperature), laser Doppler imaging (LDI, skin blood flow) and multispectral imaging (MSI, oxygenation), were performed at four sites: two of affected skin (centre and inner edge of lesion) and two of non-affected skin (one cm from edge of lesion 'outer' and contralateral non-affected side), at 4 visits at 3 monthly intervals. RESULTS: Differences between affected and non-affected skin were detected with all 4 techniques. Compared with non-affected skin, affected skin was thinner (p< 0.001) with higher temperature (p< 0.001-0.006), perfusion (p< 0.001-0.039) and oxygenation (p< 0.001-0.028). Lesion skin activity (LoSCAT) was positively correlated with centre HFUS (r = 0.32; 95% CI [0.02, 0.61]; p= 0.036) and negatively correlated with centre LDI (r=-0.26; 95% CI [-0.49, -0.04]; p= 0.022). Lesion skin damage was positively correlated with centre and inner IRT (r = 0.43; 95% CI [0.19, 0.67]; p< 0.001, r = 0.36, 95% CI [0.12, 0.59]; p= 0.003, respectively) and with centre and inner LDI (r = 0.37; 95% CI [0.05, 0.69]; p= 0.024, r = 0.41; 95% CI [0.08, 0.74]; p= 0.015, respectively). CONCLUSION: Non-invasive imaging can detect differences between affected and non-affected skin in JLS and may help to differentiate between activity (thicker, less well perfused skin) and damage (thinner, highly perfused skin).

Systemic sclerosis sine scleroderma in children.

OBJECTIVE: Juvenile systemic sclerosis (JSSc) is a rare condition in childhood and its variety with no skin involvement, sine scleroderma (ssJSSc), is anecdotal. We report the first case series of patients with ssJSSc. METHODS: Demographic, clinical and laboratory data of patients with JSSc followed at our centre were retrospectively collected. Patients with no skin involvement but with all of the features RP, positive ANA, intestinal dysmotility and/or interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH) and/or cardiac or renal involvement typical of scleroderma were defined as having ssJSSc and compared with those with classic JSSc (cJSSc). RESULTS: Among 52 JSSc patients seen in 20 years, five (9.6%) presented with ssJSSc. Their clinical features and those of the only two patients reported in the literature so far were compared with classic JSSc with available complete data. Six patients had cardiac involvement as presenting feature, three primary cardiomyopathy, three secondary to PAH. Two patients died after a brief disease course and one rapidly underwent heart transplantation. In comparison with cJSSc, ssJSSc showed a significantly longer diagnostic delay (20.1 vs 8.3 months, P = 0.017), higher frequency of cardiac involvement (85.7 vs 15.6%, P = 0.001) and worse outcome, intended as mortality or end-stage organ failure rates (42.9% vs 6.2%, P < 0.001). CONCLUSION: Cardiac involvement represents the most important characteristic of ssJSSc and carries a high morbidity and mortality rate. The longer delay in diagnosis underlines the need for a comprehensive rheumatological work-up in patients with isolated cardiomyopathy or PAH/ILD.

Proposal of an Algorithm to Early Detect Attenuated Type I Mucopolysaccharidosis (MPS Ia) among Children with Growth Abnormalities.

Background and Objectives: Diagnostic delay is common in attenuated Mucopolysaccharidosis Type I (MPS Ia) due to the rarity of the disease and the variability of clinical presentation. Short stature and impaired growth velocity are frequent findings in MPS Ia, but they rarely raise suspicion as paediatric endocrinologists are generally poorly trained to detect earlier and milder clinical signs of this condition. Materials and Methods: Following a consensus-based methodology, a multidisciplinary panel including paediatric endocrinologists, paediatricians with expertise in metabolic disorders, radiologists, and rheumatologists shared their experience on a possible clinical approach to the diagnosis of MPS Ia in children with short stature or stunted growth. Results: The result was the formation of an algorithm that illustrates how to raise the suspicion of MPS Ia in a patient older than 5 years with short stature and suggestive clinical signs. Conclusion: The proposed algorithm may represent a useful tool to improve the awareness of paediatric endocrinologists and reduce the diagnostic delay for patients with MPS Ia.

Mycophenolate mofetil for methotrexate-resistant juvenile localized scleroderma.

OBJECTIVES: To investigate safety and efficacy of MMF in patients with severe or MTX-refractory juvenile localized scleroderma. METHODS: Consecutive juvenile localized scleroderma patients undergoing systemic treatment were included in a retrospective longitudinal study. Patients treated with MMF because they were refractory or intolerant to MTX (MMF-group) were compared with responders to MTX (MTX-group). Disease activity was assessed by Localized Scleroderma Cutaneous Assessment Tool and thermography. Disease course was established on the number of relapses and treatment changes. Relapse-free survival was examined by Kaplan-Meier analysis. RESULTS: MMF and MTX groups included 22 and 47 patients, respectively. No significant difference in demographics, follow-up duration and treatment before diagnosis was observed between groups. The most represented clinical subtypes in the MMF-group were pansclerotic morphea and mixed subtype (P = 0.008 and P = 0.029, respectively), and linear scleroderma of the face in the MTX-group (P = 0.048). MMF was started because of MTX resistance (18 patients), relapse during MTX tapering/withdrawal (3 patients) and anaphylaxis to MTX (1 patient). After mean 9.4 years of follow-up, 90.9% of patients on MMF and 100% of those on MTX had inactive disease. No significant difference in relapse-free survival between the groups was found (P = 0.066, log-rank test), although MMF likely induced more persistent remission. MMF was well tolerated and combination of MMF and MTX did not increase its efficacy. CONCLUSION: The present study adds strong evidence on the efficacy and tolerance of MMF in severe and/or MTX-refractory juvenile localized scleroderma. Further controlled studies are needed to prove its efficacy as first line treatment.

Early detection of ventricular dysfunction in juvenile systemic sclerosis by speckle tracking echocardiography.

OBJECTIVE: Cardiac involvement is the most important cause of mortality in juvenile systemic sclerosis (JSSc). Recent reports in adult patients underline that traditional techniques of imaging are inadequate to assess the subclinical cardiac involvement, while speckle tracking echocardiography (STE) is able to identify ventricular dysfunctions in the early stages. The aim of our study was to assess the role of STE in JSSc. METHODS: Demographic, clinical and laboratory data were collected from patients with JSSc. Cardiac investigations performed at baseline (T0) and 18 (T18) and 36 months (T36) follow-up included electrocardiography, conventional echocardiography with measurement of the ejection fraction (EF) and STE with assessment of left and right ventricular global longitudinal strain (LV-GLS and RV-GLS). Cardiac parameters have been compared with demographic characteristics and disease severity, assessed by the Juvenile Systemic Sclerosis Severity Score (J4S). RESULTS: A total of 18 patients, 12 (67%) females, entered the study. At T0, electrocardiography was abnormal in three patients, EF was reduced in one, LV-GLS was abnormal in three (16.7%) and RV-GLS was abnormal in five (27.8%). At T18, EF remained stable while at T36 the result decreased in seven of nine patients. At the same time, LV-GLS also worsened (from -21.6% to -18.2%, P = 0.01). LV-GLS and RV-GLS at baseline showed a significant correlation with J4S (P = 0.012 and P = 0.02, respectively). CONCLUSION: STE is more sensitive than standard echocardiography to identify cardiac involvement in JSSc. Over time, we observed a gradual worsening of LV-GLS, a sign of left ventricular dysfunction, that anticipated by several months the decrease of EF.

Consensus-based recommendations for the management of juvenile systemic sclerosis.

Juvenile systemic sclerosis (JSSc) is a rare disease of childhood and currently no international consensus exists with regard to its assessment and treatment. This SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) initiative, based on expert opinion informed by the best available evidence, provides recommendations for the assessment and treatment of patients with JSSc with a view to improving their outcome. Experts focused attention not only on the skin assessment but also on the early signs of internal organ involvement whose proper treatment can significantly affect the long-term outcome. A score for disease severity is proposed in order to perform a structured assessment of outcome over time but a validation in a wider patient population is recommended. Finally, a stepwise treatment approach is proposed in order to unify the standard of care throughout Europe with the aim to reduce morbidity and mortality in this disease.

Osteoperiostitis in children: proposal for a diagnostic algorithm.

Juvenile osteoperiostites (JOP) are a group of inflammatory bone diseases whose differential diagnosis is often difficult. The main conditions are acute osteomyelitis (AOM), chronic non-bacterial osteomyelitis (CNO) and the Goldbloom syndrome (GS). The study was aimed to develop an algorithm to enable an early diagnosis of JOP. Clinical records of patients with AOM, CNO and GS, followed at our Center over the past 10 years, were reviewed. Twelve additional patients with GS were selected from PubMed/MEDLINE literature search. Data collected included demographics, clinical manifestations, laboratory and instrumental investigations at disease onset. The association between categorical variables was investigated, and the segmentation of patients with different diagnoses was analyzed through a classification tree model (CTREE package) in order to build up a diagnostic algorithm. Ninety-two patients (33 CNO, 44 AOM, 15 GS) entered the study. Among 30 variables considered at onset, nine (age at onset, fever, weight loss, symmetry, focality, functional limitation, anemia, elevated ESR, CRP) resulted statistically significant in differentiating the three clinical entities from each other and were chosen to build up a decisional tree. Three variables, symmetry of bone involvement, presence of fever and age at disease onset, resulted significant to discriminate each of the three diseases from the others. The performance of the diagnostic algorithm was validated by comparing the diagnoses provided by the model with the real diagnoses and showed 85.9% accuracy.Conclusion: We propose a diagnostic algorithm, based on simple clinical data, which can help guide a prompt and appropriate diagnosis of JOP. What is Known: • Juvenile osteoperiostitis (JOP) are a group of inflammatory bone diseases followed by various pediatric specialists. • The distinction between these conditions is not easy as clinical and laboratory features often overlap. What is New: • We propose a diagnostic algorithm, based on clinical data of real patients, with high degree accuracy. • This instrument can help guide the prompt and appropriate diagnosis of JOP.

Rituximab for rapidly progressive juvenile systemic sclerosis.

OBJECTIVE: Juvenile systemic sclerosis (JSSc) with rapidly progressive course is a life-threatening condition associated with a poor prognosis. Recently, rituximab (RTX) has been shown to be a promising treatment for adult patients with SSc. We present a series of four patients with rapidly progressive JSSc successfully treated with RTX. METHODS: Clinical, laboratory and functional parameters were collected from four patients with rapidly progressive JSSc treated with RTX for at least 1 year. All patients underwent four yearly courses of i.v. RTX 375 mg/m2 on day 0 and 14, at 3-month intervals. Low dose oral prednisone and MMF were also administered. Data were recorded at baseline and every 6 months and included pulmonary and myocardial function parameters, muscular, vascular and skin changes. The Juvenile Systemic Sclerosis Severity Score (J4S) estimated the overall disease severity over time. RESULTS: Four patients (three males, one female), aged 8-17 years, entered the study. Three patients presented with prevalent cardiac involvement, one with severe pulmonary involvement. After 1 year of RTX treatment, all patients showed significant improvement of J4S, Raynaud's phenomenon and cutaneous involvement. Among those with prevalent cardiac involvement, two showed an improvement of the myocardial function (left ventricular ejection fraction [EF] +37% and +19%, respectively) and in the third arrhythmias disappeared. The patient with severe pulmonary involvement showed a significant improvement of the respiratory function (forced vital capacity +46%, forced expiratory volume in 1 s +33%, diffusing capacity of the lung for carbon monoxide [DLCO] +30%). No major side effects were reported. CONCLUSIONS: Our data suggest that a combination of RTX and MMF is effective in arresting the rapid progression of JSSc.

Sarcopenia in juvenile localized scleroderma: new insights on deep involvement.

OBJECTIVES: Juvenile localized scleroderma (JLS) is a rare chronic autoimmune disease which can also affect bones and muscles. Nevertheless, muscle loss was not previously investigated in patients with JLS. Thus, the aim of this study was to retrospectively evaluate deep involvement and assess and quantify sarcopenia in JLS patients using magnetic resonance imaging (MRI). METHODS: Fourteen children with JLS (nine females, mean age ± SD, 7.1 ± 3.6 years) referring to our tertiary center from January 2012 to January 2018 who underwent at least one MRI examination including axial T1-weighted and short tau inversion recovery images were included. Two readers assessed in consensus superficial and deep involvement. Muscle edema, muscle fatty infiltration, and sarcopenia were independently scored (absent, moderate, or severe) and the Cohen's kappa coefficient computed. Skin perimeter, subcutaneous area, muscle area, and muscle volume were independently measured using the contralateral unaffected extremity as reference (paired Student's t test, p < 0.05). The intraclass correlation coefficient (ICC) was used to investigate the reliability of the measurements. RESULTS: All patients showed superficial involvement with subcutaneous fat atrophy being the most common finding (13 patients). Bone marrow edema occurred in five patients. Muscle edema affected ten children (moderate in seven, severe in three; k = 0.89), muscle fatty replacement occurred in one case (severe; k = 1.00), and sarcopenia was detected in eight patients (severe in two; k = 0.78). All quantitative parameters were lower on the affected side than on the unaffected contralateral limb (p < 0.05, each) and all measurements showed a high reliability (ICC > 0.750, each). CONCLUSION: Patients with JLS can be affected by sarcopenia and quantitative analyses allow a robust characterization of such finding. KEY POINTS: • Deep involvement in juvenile localized scleroderma is frequently characterized by sarcopenia. • In juvenile localized scleroderma, muscle edema and sarcopenia are mostly moderate while fatty infiltration, even if rare, can be severe. • Sarcopenia can be reliably quantified in children with juvenile localized scleroderma using MRI.

Treatment in Juvenile Scleroderma.

PURPOSE OF REVIEW: Treatment of scleroderma in children is challenging since little is known about its pathogenesis. Herein, we review the most recent evidence regarding the treatment of juvenile scleroderma. RECENT FINDINGS: According to the recent recommendations for Pediatric Rheumatology in Europe (SHARE), systemic treatment in localized scleroderma is needed when there is a risk for disability, such as in generalized or pansclerotic morphea and progressive linear scleroderma. In juvenile systemic sclerosis, the introduction of the severity score, J4S, has standardized the assessment of the patients in the daily practice and allowed a more tailored therapeutic approach. Since, to date, no clinical trial is available in JSSc, due to its rarity, the treatment is based on adults' experience. The recent recommendations for juvenile scleroderma represent an important instrument to standardize the treatment approach, confirm the role of methotrexate, and open new windows for effective experimental treatments, such as mycophenolate mofetil and biological agents, for severe or refractory cases.

Consensus-based recommendations for the management of juvenile localised scleroderma.

In 2012, a European initiative called Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile localised scleroderma (JLS) is a rare disease within the group of paediatric rheumatic diseases (PRD) and can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. This study aims to provide recommendations for assessment and treatment of JLS. Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was formed, mainly from Europe, and consisted of 15 experienced paediatric rheumatologists and two young fellows. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at two consensus meetings using a nominal group technique. Recommendations were accepted if ≥80% agreement was reached. In total, 1 overarching principle, 10 recommendations on assessment and 6 recommendations on therapy were accepted with ≥80% agreement among experts. Topics covered include assessment of skin and extracutaneous involvement and suggested treatment pathways. The SHARE initiative aims to identify best practices for treatment of patients suffering from PRDs. Within this remit, recommendations for the assessment and treatment of JLS have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JLS throughout Europe.

The European network for care of children with paediatric rheumatic diseases: care across borders.

OBJECTIVES: To provide an overview of the paediatric rheumatology (PR) services in Europe, describe current delivery of care and training, set standards for care, identify unmet needs and inform future specialist service provision. METHODS: An online survey was developed and presented to national coordinating centres of the Paediatric Rheumatology International Trials Organisation (PRINTO) (country survey) and to individual PR centres (centre and disease surveys) as a part of the European Union (EU) Single Hub and Access point for paediatric Rheumatology in Europe project. The survey contained components covering the organization of PR care, composition of teams, education, health care and research facilities and assessment of needs. RESULTS: Response rates were 29/35 (83%) for country surveys and 164/288 (57%) for centre surveys. Across the EU, approximately one paediatric rheumatologist is available per million population. In all EU member states there is good access to specialist care and medications, although biologic drug availability is worse in Eastern European countries. PR education is widely available for physicians but is insufficient for allied health professionals. The ability to participate in clinical trials is generally high. Important gaps were identified, including lack of standardized clinical guidelines/recommendations and insufficient adolescent transition management planning. CONCLUSION: This study provides a comprehensive description of current specialist PR service provision across Europe and did not reveal any major differences between EU member states. Rarity, chronicity and complexity of diseases are major challenges to PR care. Future work should facilitate the development, dissemination and implementation of standards of care, treatment and service recommendations to further improve patient-centred health care across Europe.

Natural history and extracutaneous involvement of congenital morphea: Multicenter retrospective cohort study and literature review.

BACKGROUND: Congenital morphea is a form of localized scleroderma that presents at birth. There is limited information on its presentation and progression. METHODS: Patients with congenital morphea were identified from five pediatric dermatology and rheumatology tertiary care centers in Canada, the United States, and Italy from 2001 to 2016. Cases from the literature were identified by searching Ovid (EMBASE and MEDLINE) from inception to June 30, 2017. Disease characteristics and prevalence of extracutaneous involvement were analyzed. RESULTS: Thirteen patients were identified from the five centers, and 13 cases were described in the literature, representing 25 patients, with one duplication. Fourteen patients (56%) were female. Median age at diagnosis was 2.9 years (interquartile range 1.2-5.1 years). Linear morphea, including en coup de sabre and Parry-Romberg syndrome, was the most common subtype observed (n = 19, 76%), followed by circumscribed (n = 5, 20%), generalized (n = 2, 8%), and mixed (n = 2, 8%). The face (n = 14, 56%), scalp (n = 8, 32%), and trunk (n = 6, 24%) were the most common locations affected. Most lesions were active at diagnosis (n = 19, 76%), but all patients with follow-up later became inactive. Extracutaneous involvement was seen in 12 (48%) patients, all of whom had linear morphea. Musculoskeletal sequelae were seen in those with linear morphea of the extremities (4/5, 80%), and neurologic involvement was seen in those with linear morphea of the head (8/13, 62%). CONCLUSION: Congenital morphea is associated with extracutaneous manifestations and delayed diagnosis. More research is needed to determine whether early recognition, monitoring, and treatment can alter the disease course.

Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial.

BACKGROUND: Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis. METHODS: We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedman's test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960. FINDINGS: Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. INTERPRETATION: Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. FUNDING: Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).

Update of EULAR recommendations for the treatment of systemic sclerosis.

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

Tocilizumab in two children with pansclerotic morphoea: a hopeful therapy for refractory cases?

Pansclerotic morphoea (PM) is a subtype of juvenile localised scleroderma characterised by severe course with generalised full-thickness skin involvement and possible growth and functional impairment. PM treatment comprises a combination of immunosuppressive agents such as corticosteroids, methotrexate, mycophenolate mofetil, PUVA and antithymocyte globulin and biological agents used in off-label. A possible role of IL-6 in the regulation of firoblast differentiation and stimulation of collagen synthesis has been suggested and in patients with systemic sclerosis (SSc) the treatment with tocilizumab (TCZ) was associated to improvement of skin thickness and joint motion. We describe the first two cases of children with PM refractory to different immunosuppressive agents in which the use of TCZ reduced disease activity and stopped disease progression. Therefore, we suggest that an earlier use of this agent in such severe cases could be considered before irreversible sclerosis and tissue damage occurs.Juvenile localised scleroderma (JLS) comprises a group of autoimmune fibrosing conditions involving skin and subcutaneous tissues following an initial inflammatory reaction. Pansclerotic morphoea (PM), an extremely rare and severe subtype of JLS, is characterised by generalised full-thickness skin involvement that may extend over deeper tissues and bone with subsequent growth disturbance and disabling outcome. We describe the first two children with PM refractory to immunosuppressive treatments in which the off-label use of tocilizumab (TCZ), fully humanised anti IL-6R antibody, allowed to control the inflammation and stopped the extension of the disease.

Joint hypermobility and oligoarticular juvenile idiopathic arthritis: What relationship?

AIM: Oligoarticular onset juvenile idiopathic arthritis (oJIA) is characterised by a prevalent lower limb involvement, antinuclear antibodies (ANA) positivity and high risk of anterior uveitis. As we observed that oJIA patients frequently present with joint hypermobility (JH), we investigated whether there was a relationship between oJIA and JH. METHODS: Our series consisted of children with oJIA, as defined by the International League of Associations for Rheumatology criteria, for whom complete clinical data of at least 2 years' duration were available. Clinical and laboratory data, collected at disease onset and at the last follow-up, included: sex, age, presence of JH according to the Beighton score, disease activity, presence of uveitis, ANA, treatment and outcome. RESULTS: A total of 274 oligoarticular JIA patients (224 female, 50 male; mean age: 11.5) followed on average for 6.6 years, entered the study. The mean age at disease onset was 4.9 years, ANA were positive in 83.9% and uveitis occurred in 20.8%. JH was present in 70.8% of cases at onset, in 44.5% at the last evaluation. JH was more frequent in females (73.7%) than in males (58.0%) (P = 0.028). Uveitis was less frequent in hypermobile children both at diagnosis (17.5 vs. 28.7%, P = 0.037) and during overall disease course (23.7 vs. 36.3%, P = 0.034). Of 163 subjects with at least 5-year follow-up, the full clinical remission rate was significantly higher in JH patients (50.5%) than in those without JH (42.3%; P = 0.042). CONCLUSION: In patients with oligoarticular JIA, JH is more frequent than in healthy subjects, uveitis less frequent and the long-term outcome better.