Mixed connective tissue disease (MCTD) is a complex overlap disease with features of different autoimmune connective tissue diseases (CTDs) namely systemic sclerosis, poly/dermatomyositis and systemic lupus erythematous in patients with antibodies targeting the U1 small nuclear ribonucleoprotein particle. In this narrative review, we summarise the results of a systematic literature research which was performed as part of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases project, aimed at evaluating existing clinical practice guidelines (CPGs) or recommendations. Since no specific CPGs on MCTD were found, other CPGs developed for other CTDs were taken into consideration in order to discuss what can be applied to MCTD even if designed for other diseases. Three major objectives were proposed for the future development of CPGs: MCTD diagnosis (diagnostic criteria), MCTD initial and follow-up evaluations, MCTD treatment. Early diagnosis, epidemiological data, assessment of burden of disease and QOL aspects are among the unmet needs identified by patients.

Objective To report the effort of the European Reference Network for Rare and Complex CONnective tissue and musculoskeletal diseases NETwork working group on Ehlers-Danlos syndromes (EDS) and related disorders to assess current available clinical practice guidelines (CPGs) specifically addressed to EDS, in order to identify potential clinician and patient unmet needs. Methods Systematic literature search in PUBMED and EMBASE based on controlled terms (MeSH and Emtree) and keywords of the disease and publication type (CPGs). All the published articles were revised in order to identify existing CPGs on diagnosis, monitoring and treatment of EDS. Results Literature revision detected the absence of papers reporting good quality CPGs to optimise EDS patient care. The current evidence-based literature regarding clinical guidelines for the EDS was limited in size and quality, and there is insufficient research exploring the clinical features and interventions, and clinical decision-making are currently based on theoretical and limited research evidences. Conclusions Many clinician and patient unmet needs have been identified.

Antiphospholipid syndrome (APS) is a rare disease characterised by venous and/or arterial thrombosis, pregnancy complications and the presence of specific autoantibodies called antiphospholipid antibodies. This review aims to identify existing clinical practice guidelines (CPG) as part of the ERN ReCONNET project, aimed at evaluating existing CPGs or recommendations in rare and complex diseases. Seventeen papers providing important data were identified; however, the literature search highlighted the scarceness of reliable clinical data to develop CPGs. With no formal clinical guidelines in place, diagnosis and treatment of APS is largely based on consensus and expert opinion. Patients’ unmet need refers to the understanding of the disease and its clinical picture and implications, the need of education for patients, family members and healthcare providers, as well as to the development of monitoring pathways involving multiple healthcare providers.

Objective. To revise the current juvenile idiopathic arthritis (JIA) International League of Associations for Rheumatology (ILAR) classification criteria with an evidence-based approach, using clinical and routine laboratory measures available worldwide, to identify homogeneous clinical groups and to distinguish those forms of chronic arthritis typically seen only in children from the childhood counterpart of adult diseases. Methods. The overall project consists of 4 steps. This work represents Step 1, a Delphi Web-based consensus and Step 2, an international nominal group technique (NGT) consensus conference for the new provisional Pediatric Rheumatology International Trials Organization JIA classification criteria. A future large data collection of at least 1000 new-onset JIA patients (Step 3) followed by analysis and NGT consensus (Step 4) will provide data for the evidence-based validation of the JIA classification criteria. Results. In Step 1, three Delphi rounds of interactions were implemented to revise the 7 ILAR JIA categories. In Step 2, forty-seven questions with electronic voting were implemented to derive the new proposed criteria. Four disorders were proposed: (a) systemic JIA; (b) rheumatoid factor–positive JIA; (c) enthesitis/spondylitis-related JIA; and (d) early-onset antinuclear antibody–positive JIA. The other forms were gathered under the term “others.” These will be analyzed during the prospective data collection using a list of descriptors to see whether the clustering of some of them could identify homogeneous entities. Conclusion. An international consensus was reached to identify different proposed homogeneous chronic disorders that fall under the historical term JIA. These preliminary criteria will be formally validated with a dedicated project.

Introduction: Juvenile systemic sclerosis is an orphan disease. Currently, the majority of juvenile systemic sclerosis cohort studies are retrospective in design without standardized assessment. This study was conducted prospectively to investigate the difference in manifestations of limited cutaneous juvenile systemic sclerosis and diffuse cutaneous juvenile systemic sclerosis subtypes. An additional aim was to compare these data to other juvenile systemic sclerosis cohorts and a large adult systemic sclerosis cohort. Methods: Patients fulfilling the Paediatric Rheumatology European Society juvenile systemic sclerosis classification criteria were included. Clinical characteristics and patient-related outcomes were assessed. Results: In all, 88 patients with a mean disease duration of 3.5 years were enrolled, 72.5% with diffuse cutaneous juvenile systemic sclerosis with a mean modified Rodnan Skin score of 18 and 27.5% with limited cutaneous juvenile systemic sclerosis with mean modified Rodnan Skin score of 9. The mean age at the onset of Raynaud’s and first non-Raynaud’s symptoms was similar in both groups, approximately 9 and 10.5 years. Active digital tip ulcerations were present in 29% diffuse cutaneous juvenile systemic sclerosis and none in the limited cutaneous juvenile systemic sclerosis subjects (p = 0.005). Of those with cardiopulmonary testing, 3% of diffuse cutaneous juvenile systemic sclerosis and 23% of limited cutaneous juvenile systemic sclerosis group had cardiac involvement (p = 0.015), and 41% diffuse cutaneous juvenile systemic sclerosis and 22% of the limited cutaneous juvenile systemic sclerosis group had pulmonary involvement (p = 0.009). Physician global disease damage assessment was higher in the diffuse cutaneous juvenile systemic sclerosis group compared to the limited cutaneous juvenile systemic sclerosis group: 35 and 15 (p = 0.021). Discussion: The majority of this international juvenile systemic sclerosis cohort had diffuse cutaneous juvenile systemic sclerosis (72.5%) with more frequent vascular and pulmonary involvement compared to the limited cutaneous group, who had increased cardiac involvement. Our cohort reflects prior findings of published juvenile systemic sclerosis cohorts and emphasizes a difference in the presentation compared to adult-onset systemic sclerosis.

Background There is international consensus around a core set of variables (cSLE-CRVs) to assess response to therapy with childhood-onset systemic lupus erythematosus (cSLE) [global assessment of patient well-being (Patient-global), physician assessment of cSLE activity (MD-global), disease activity index score, urine protein to creatinine ratio (PCR), Child Health Questionnaire physical function summary score (CHQ-Phs)]. Percentage changes of these cSLE-CRVs are used in the Provisional PRINTO-ACR- EULAR Criteria of Response to Therapy of cSLE (PCI). In a small dataset, we have previously shown that the PCI and the Systemic Lupus Responder Index only have fair accuracy in detecting cSLE improvement. The Objective of this research was to 1) validate the PCI and 2) develop for Children an Index of Lupus Improvement (CHILI) as a tool to measure response to therapy, with focus on clinically relevant improvement (CRIcSLE). Methods Pediatric subspecialists (n=213) in treating cSLE were invited to define CRIcSLE and rate a total of 433 unique patient profiles for the presence/absence of CRIcSLE and various levels of improvement. Patient profiles included the cSLE-CRVs and routine laboratory tests at a baseline and follow-up time-point. To measure CRIcSLE we tested the PCI, and developed the candidate CHILI criteria that considered a) absolute and b) percentage changes of the cSLE-CRVs (baseline vs follow-up) in a trainings-dataset and initially validated these criteria in the validation-dataset. Criteria accuracy was assessed by kappa statistics (PCI) and the area under the ROC curve (AUC; range: 0–1)], respectively. Results During an international consensus conference agreement on a definition of CRIcSLE was achieved. Response rate to patient profile ratings was 91% (194/214). The PIC had no more than fair accuracy (kappa 0.92, sensitivity: >93.1%; specificity: >73.4%), respectively. Conclusions The CHILI is a new highly accurate index to capture improvement in the overall course of cSLE. This index is also useful to categorize the degree of cSLE response to therapy. Acknowledgements For the Pediatric Rheumatology International Trial Network and the Pediatric Rheumatology Collaborative Study Group; the study is supported by NIH grants 5U01-AR51868, P30-AR AR47363 and 2UL1RR026314 and the PRCSG and PRINTO Coordinating Centers. This study is also supported by grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP 2015/03756–4 to CAS), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq 303422/2015–7 to CAS) and by Nucleo de Apoio a Pesquisa ‘Saude da Crianca e do Adolescente’ da USP (NAP-CriAd) to CAS.

The pathogenesis, clinical course, and response to treatment in systemic juvenile idiopathic arthritis (SJIA) differ from other types of juvenile idiopathic arthritis and are similar to other interleukin-1 (IL-1)-mediated diseases. The main cytokine involved in the pathogenesis of SJIA is IL-1β, which can be neutralized by targeted anti-IL-1 therapy. In SJIA, no antibodies have been found and there is growing evidence that it is mainly an autoinflammatory and not an autoimmune disease. Before the era of biologic therapy, treatment of SJIA was primarily based on long-term treatment with high doses of glucocorticosteroids (GCS). The side effects of GCS could have a significant impact on the outcome of the disease and could cause long-term damage. Treatment with anti-IL-1 agents early in the disease course has revolutionized the management principles of SJIA. However, not all SJIA patients respond equally well to anti-IL-1 therapy, and it has been shown that age at the onset of disease, duration of the disease, number of affected joints, neutrophil count, and ferritin level can predict the response to anti-IL-1 therapy. In particular, an elevated ferritin level should prompt testing for macrophage activation syndrome (MAS), the most severe complication of SJIA. Anti-IL-1 therapy has been shown to be effective also in patients with MAS. Although anti-IL-1 agents are currently not recommended as first-line treatment, there is growing evidence that anti-IL-1 agents introduced at the beginning of SJIA could enable lower doses and a shorter duration of GCS therapy, change the long-term disease outcome, and even influence molecular disease patterns. There are currently three anti-IL-1 agents available: anakinra, canakinumab, and rilonacept. In this review, we present the current knowledge on the pathogenesis of SJIA, the rational for anti-IL-1 treatment, and future perspectives on the treatment of SJIA.

Background Juvenile systemic scleroderma (jSSc) is an orphan disease, with an estimated prevalence of 3 per 1000 000 children. Most jSSc patients primarily present with Raynaud phenomenon (RP). We investigated in our patient of the juvenile scleroderma inception cohort, how fare patients with (RP+) and without (RP-) RP differed in their clinical presentation at enrolment. Methods The jSSc is a prospective cohort of jSSc patients. Patients were enrolled who were diagnosed with jSSc, had a jSSc onset age under 16 years and were younger as age of 18 years at the time of inclusion. The patients are prospectively assessed every 6 months according to a standardised protocol. We reviewed the organ involvement pattern of our patients currently followed in the cohort. Results 100 patients are currently followed in the cohort and 89 (89%) of them had RP. The female/male ratio was lower in the RP +group, 3.7:1 compared to 4.5:1(p=0.808). Diffuse subtype was more common in the RP +group, 72% compared to 63%. Mean age of onset of first non- Raynaud symptomatic was 10.4 years in both groups. Mean disease duration was slightly higher in the RP +group, 3.4 compared to 2.2 years. ANA positivity was higher in the RP +group, 88% compared to 70% (p=0.48). Anti-Scl70 was 34% in the RP +and 20% in the RP-group (p=0.34). Interestingly 7% of RP +but none of the RP +were anti-centromere positive. The mean modified skin score was lower in RP +group (mean of 14.8 compared to 17.0). There were significantly more nailfold capillary changes (70% compared to 18%, p=0.001) and a higher rate of history of ulceration in the RP +group (49% compared to 20%, p=0.083). Decreased DLCO and FVC <80% was higher in the RP-negative group with 45%/50% compared to 37.5%/31% respectively. Pulmonary hypertension occurred in 7% in the RP +group and there was no case in the RP- group (p=0.335). RP- group had a higher rate of urinary sediment changes 18% compared to 4.5% in the RP +group (p=0.07). No renal crisis or hypertension was reported in neither groups. Gastrointestinal involvement was similar between the two groups with around 35%. Occurrence of swollen joints was similar in both groups as the frequency of muscle weakness with around 20%. The tendon friction rub occurred around 10% in both groups. In the patient related outcomes, there was only a difference in rating of Raynauds activity. Conclusions The RP– group differed from RP +group in the clinical presentation at enrolment. The absence of Raynaud phenomenon was associated with a decreased rate of history of ulceration, no occurrence of pulmonary hypertension. Interestingly higher rate of urinary sedimentary changes and no anticentromere positivity was observed in RP- patients. Disclosure of Interest None declared

Background Juvenile systemic scleroderma (jSSc) is an orphan disease with an estimated prevalence of around 3 per 1 000 000 children. There are no studies which evaluated prospectively the patient related outcomes in these patients. We report the data from juvenile scleroderma inception cohort (jSSc) regarding organ involvement and patient related outcomes. Methods The jSSc is a prospective cohort of jSSc patients. Patients were enrolled who were diagnosed with jSSc, had a jSSc onset age under 16 years and were younger as age of 18 years at the time of inclusion. The patients are prospectively assessed every 6 months according to a standardised protocol. Patients with available 12 months follow up data were included in the analyses. Results Currently 100 patients are followed in the jSSc cohort. 51 of them had available 12 months follow up data. Among those patients 37 (72.5%) had diffuse and 14 (27.5%) limited subtype. Mean age of onset of disease was 9.5 (±4.1) years and the mean disease duration at time of inclusion was 3.1 years (±3.2). The proportion of patients treated with DMARD increased from 74.5% to 88% at 12 months follow up. 86% were ANA positive at both assessments. Anti-scl70 positivity increased from 38% to 42%. Anticentromere antibody positivity was 2.4% at both assessments. Mean modified skin score decreased from 17.7 to 14.3 (p=0.151) Raynaud phenomenon occurred in 86% at enrolment and increased up to 88% at 12 months follow up. Nailfold capillary changes occurred around 70% at both assessments, but number of patients with active ulceration decreased from 28% to 16% (p=0.148). The number of patients with decreased FVC (FVC under 80%) decreased from 40.5% to 32% (p=0.497). The number of patients with pulmonary hypertension remained around 10%. No renal crisis or hypertension were reported. The gastrointestinal involvement was around 40% at both assessments. The number of patients with swollen joints decreased from 24% to 10% (p=0.06). The number of patients with muscle weakness decreased significantly from 33% to 9% (p=0.016), parallel to the number of patients with elevated CK values which decreased from 27% to 12% (p=0.074). All patient related outcomes, like global disease activity (p=0.048), global disease damage (p=0.05), Raynaud activity (p=0.003) and ulceration activity (p=0.001) improved significantly over 12 months. Physician assessed global disease activity (p=0.003) and ulceration activity (p=0.001) also improved significantly. Conclusions Our data show, that jSSc patients over a 12 months disease course stayed quite stable or improved regarding organ involvement. But patient and physician related outcomes regarding activity assessment improved significantly. Disclosure of Interest None declared

Background At present no clear evidence based guidelines exist to standardise the tapering and discontinuation of corticosteroids (CS) in juvenile dermatomyositis (JDM). Objectives To provide evidence-based recommendations for CS tapering/discontinuation through the analysis of the patients in the PRINTO new onset JDM trial. Secondary objective of the study was to identify predictors of clinical remission and CS discontinuation. Methods New onset JDM children were randomised to receive either prednisone (PDN) alone or in combination with MTX or CSA. All children were given initially intravenous methylprednisolone, and then PDN starting with 2 mg/kg/day. Gradual tapering according to a specific protocol could lead to the safe dose of 0.2 mg/kg/day by month 6, then discontinued at month 24. Major therapeutic changes (MTC) were defined as the addition or major increase in the dose of MTX/CSA/other drugs or any other reasons for which patients were dropped from the trial. Patients were divided according to clinical remission (CR) (CMAS=52 and MD global=0 for 6 continuous months) into two major groups. Group 1 included those on CR, who could discontinue PDN, with no MTC (reference group). Group 1 was compared with those who did not achieve CR, without or with MTC (group 2 and 3, respectively). JDM core set measures (CSM) were compared within the 3 groups. We also calculated the gold standard group 1 median change in the CSM in the first 6 and over 24 months and applied a logistic regression model to identify predictors of CR with PDN discontinuation. Results 139 children were enrolled in the trial: 47 on PDN, 46 on PDN +CSA and 46 on PDN +MTX. We identified 30 (21.6%) patients for group 1, 43 (30.9%) for group 2 and 66 (47.5%) for group 3. At baseline all 3 groups had no differences in the CSM. Already in the first 2 months a clear differential trend in disease activity measures, according to clinical remission status and PDN discontinuation, could be identified. From the observation of the median change in the CSM of group 1 in the first 6 months, the following recommendations could be extrapolated: decrease corticosteroids from 2 to 1 mg/kg/day in 2 months if the MD-global, parent-global, CHAQ, DAS, CMAS, MMT or Phs measures have changed of at least 50%; from 1 to 0.5 mg/kg/day in the following 2 months if the MD-global, CHAQ, DAS, CMAS show a change of at least 20%; in the following 2 months (month 4–6) corticosteroids can be tapered up to the safe dose of 0.2 mg/kg/day, if the disease activity measures remain at low/normal values. We finally ran a logistic regression model that showed that the achievement of PRINTO criteria 50–70–90 at 2 months from disease onset, an age at onset >9 years and the combination therapy PDN +MTX, increase the probability of clinical remission from 4 to 7 times (table 1).Abstract OP0340 – Table 1 Logistic regression model for the outcome: achievement of remission (n/tot: 28/130; 21.5%) Conclusions We propose evidence based specific cut-offs for corticosteroid tapering/discontinuation based on the change in JDM CSM of disease activity, and to identify the best predictors for clinical remission and corticosteroid discontinuation. Disclosure of Interest None declared

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Slovene language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the 3 Likert assumptions, floor/ceiling effects, internal consistency, Cronbach’s alpha, interscale correlations, test–retest reliability, and construct validity (convergent and discriminant validity). A total of 100 JIA patients (7.0% systemic, 47.0% oligoarticular, 22.0% RF negative polyarthritis, 24.0% other categories) and 120 healthy children, were enrolled. The JAMAR components discriminated well healthy subjects from JIA patients, except for the Health-Related Quality of Life, Psychosocial Health subscales. All JAMAR components revealed good psychometric performances. In conclusion, the Slovene version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Background Prevalence of complement deficiencies (CDs) is markedly higher in Slovenian primary immunodeficiency (PID) registry in comparison to other national and international PID registries. Objective The purposes of our study were to confirm CD and define complete and partial CD in registered patients in Slovenia, to evaluate frequency of clinical manifestations, and to assess the risk for characteristic infections separately for subjects with complete and partial CD. Methods CD was confirmed with genetic analyses in patients with C2 deficiency, C8 deficiency, and hereditary angioedema or with repeated functional complement studies and measurement of complement components in other CD. Results of genetic studies (homozygous subjects vs. heterozygous carriers) and complement functional studies were analyzed to define complete (complement below the level of heterozygous carriers) and partial CD (complement above the level of homozygous patients). Presence of characteristic infections was assessed separately for complete and partial CD. Results Genetic analyses confirmed markedly higher prevalence of CD in Slovenian PID registry (26% of all PID) than in other national and international PID registries (0.5–6% of all PID). Complement functional studies and complement component concentrations reliably distinguished between homozygous and heterozygous CD carriers. Subjects with partial CD had higher risk for characteristic infections than previously reported. Conclusion Results of our study imply under-recognition of CD worldwide. Complement functional studies and complement component concentrations reliably predicted risk for characteristic infections in patients with complete or partial CD. Vaccination against encapsulated bacteria should be advocated also for subjects with partial CD and not limited to complete CD.