Juvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of around 3 in 1, 000,000 children. It is known that in pediatric jSSc cohorts, there are a significant number of patients with overlap features, such as arthritis and myositis. However, the disease burden between those with and without overlap features in jSSc has not been defined.Compare the clinical phenotype between children with and without overlap features in the juvenile systemic scleroderma inception cohort (jSScC).A cross-sectional study was performed using baseline visit data. Demographic, organ system evaluation, autoantibody profile, treatment, and patient and physician reported outcome variables were extracted from jSScC. Comparison between patients with and without overlap features was performed using chi-square test and Mann Whitney U-test.At the time of data extraction, 175 jSSc patients were enrolled in the cohort, 81% were Caucasian and 81% female. Mean disease duration was 3.1 year (±2.7). Mean age at Raynaud´s onset was 10 years (±3.8) and mean age of first non-Raynaud´s was 10.2 years (±3.8). Overlap features occurred 17% (n=30) of the cohort, 12.5% in the diffuse cutaneous (dc) jSSc and in 30% in the limited cutaneous (lc) jSSc. Significant differences in clinical characteristics were found between those patients with compared to without overlap characteristics. Patients with overlap features presented more frequently with Gottron papules (p=0.007), swollen joints (p=0.019), muscle weakness (p=0.003), and lung involvement documented by decreased DLCO < 80% (p=0.06) and/or abnormal high resolution computed tomography (p=0.049). Anti-PM/Scl autoantibodies were also more common in this group (p=0.001). Significantly more patients without overlap features had Raynaud´s (p=0.006). Physician Global Assessment of disease activity was significantly higher in patients with overlap features (41 vs 34; p=0.041). (Table 1.)Table 1.Demographic and clinical characteristics of jSSc patients with and without overlap features.Whole CohortN=175Patients without overlapN=145Patients with overlapN=30P valueFemale to Male Ratio 4.3:1(142/33)4:1(116/29)6.5:1(26/4)0.395Cutaneous subtypeDiffuse subtype (N)73% (128)11216Limited subtype (N)27% (47)3317Mean disease duration (years)3.1 (± 2.7)3.2 (± 2.8)3.1 (± 2.2)0.291Mean age of onset of Raynaud´s (years)10.0 (± 3.8)17 non-Raynaud10.0 (± 3.8)10 non-Raynaud10.0 (± 3.7)7 non-Raynaud0.931Mean age of onset of non-Raynaud´s (years)10.2 (± 3.8)10.2 (± 3.9)9.8 (± 3.7)Disease modifying drugs (N)88% (154) 89% (129)83% (25)0.388Raynaud´s phenomenon90% (158)93% (135)77% (23)0.006Anti-PMScl18% (12/68)9% (5/53)47% (7/15)0.001Gottron Papules (N)27% (46/171)23% (33/144)48% (13/27)0.007DLCO <80% (N)44% (39/88)39% (28/71)65% (11/17)0.06Abnormal findings in HRCT (N)44% (59/133)40% (43/107)62% (16/26)0.049Proportion of patients with swollen joints 18% (32) 14% (21) 37% (11)0.019Muscle Weakness (N) 21% (31/149)16% (20/123) 42% (11/26)0.003Physician global disease activity(0-100) min -max35 (0-90) n=14134 (0-90) n=11441 (0-80) n=270.041Results from this large international cohort of jSSc patients demonstrate significant differences between patients with and without overlap features. Patients with overlap have significantly more interstitial lung disease and more physician rated disease activity and should not be considered to have more “mild disease”.Supported by the “Joachim Herz Stiftung”None declared

Background: Multisystem inflammatory syndrome in children (MIS-C) was recognized during the 2020 pandemic of SARS-CoV-2. Because of the relative rarity current knowledge is limited, especially in the European Caucasian population. Objectives: To report the epidemiology, clinical and laboratory characteristics of patients with MIS-C in a nationwide cohort study in Slovenia. Methods: This is a nationwide prospective cohort study of all consecutive patients with MIS-C, admitted from the beginning of epidemics to 31st December 2020 to University Medical Centre Ljubljana, Slovenia, the only tertiary care pediatric rheumatology center in the country. The inclusion criteria were meeting the CDC criteria for MIS-C. Infection with SARS-CoV-2 was confirmed in all patients by positive antibodies for SARS-CoV-2. Data were collected from the patients' medical records. Data on the COVID-19 epidemics in Slovenia were collected from National Institute of Public Health. Population data were provided by the Statistical Office of the Republic of Slovenia. Results: Twenty-three patients with MIS-C were diagnosed nationwide in Slovenia, all of them in the second wave of epidemics from 14th September to 31st December 2020. All patients were Caucasian and the estimated prevalence of MIS-C was 5.8/100 000 persons younger than 19 years of age. Detailed analyses were available in 20 patients of which 14 were boys (70 %), median age was 12.4 years (4 months to 17.7 years). Two patients (10 %) were treated in the intensive care unit and none of the patients died. Troponin was elevated in 15/20 (75 %) patients during the disease course, and 7/15 (47 %) of these had normal troponin level at admission. The serum level of troponin closely followed the serum level of CRP. Six out of 20 (30 %) patients had elevated pancreatic enzymes in the second week of the disease after treatment was already given,and one patient developed asymptomatic acute pancreatitis with serum lipase level reaching the maximum of 25μkat/L. All patients had elevated levels of D-dimer with no signs of thrombosis. Five patients (5/20;25 %) had pleural effusions and five patients (5/20, 25 %) had ascites. Half of the patients (10/20;50 %) had hepatosplenomegaly and eight (8/20;40 %) had mesenterial lymphadenopathy. Three patients (3/20;15 %) had radiologic signs of cholecystitis. Two patients had thickened lung parenchyma. All patients received IVIG and systemic glucocorticosteroids. Because of resistant or organ threatening disease 4 patients (4/20, 20%) received high dose methylprednisolone pulse therapy. Biologic therapy with anakinra was started in 2 patients. Nineteen patients (19/20, 95%) received acetylsalicylic acid and prophylactic anticoagulation was prescribed in 15/20 (75%) of patients. The mean follow up was 50 days (14 -122). At the last follow-up visit all patients had normal laboratory parameters of inflammation, troponin, pro-BNP, d-dimer values and normal heart function. Conclusion: A very high incidence of MIS-C, estimated 5.8/100 000 persons under the age of 19 with a predominantly cardiac involvement but very good outcome was noted in European Caucasian population in a nationwide cohort study in Slovenia. Attention to newly described pancreatic involvement should be raised.

Juvenile systemic sclerosis (jSSc) is a rare disease with a prevalence of around 3 in 1,000,000 children. To better capture the clinical manifestations of jSSc the juvenile systemic sclerosis inception cohort (jSScC) has been prospectively enrolling patients with predetermined clinical variables over the past 12 years. One of the goals is to study the demographic, clinical features, and physician and patient reported outcome differences between those with juvenile limited cutaneous (lc) compared to diffuse cutaneous (dc) disease subtypes, to determine if characteristics are similar or different between dc and lc jSSc.Evaluation of the baseline clinical characteristics of jSSc patients in the jSScC. Compare clinical phenotype between diffuse (dcjSSc) and limited cutaneous (lcjSSc) subtypes.Demographic, physical examination, organ system evaluation, autoantibody profile, treatment, and patient and physician reported outcome variables were evaluated from the jSSc Inception cohort and summary statistics applied using chi-square test and Mann Whitney U-test comparing lcjSSc and dcjSSc subtypes.At the time of data extraction, 175 jSSc patients were enrolled in the cohort, 81% were Caucasian and 81% female. Diffuse cutaneous jSSc subtype predominated (73%). Mean disease duration was 3.1 year (±2.7). Mean age at Raynaud´s was 10 years (+3.8) and mean age of first non-Raynaud´s was 10.2 years (±3.8). Significant differences were found between dcjSSc versus lcjSSc, regarding several clinical characteristics. Patients with diffuse cutaneous subtype had significantly higher modified Rodnan skin score (p=0.001), presence of sclerodactyly (p=0.02), presence of Gottron’s papules (p=0.003), presence of telangiectasia (p=0.001), history of digital tip ulceration (p=0.01), and frequency of elevated CK value (p=0.04). Cardiac involvement was significantly higher in limited cutaneous jSSc subtype (p=0.02). Diffuse cutaneous jSSc patients had significantly worse scores for Physician Global Assessment of disease activity (38 vs 25; p=0.002) and disease damage (34 vs 19; p=0.008).Table 1.Comparison of demographic data and significant differences between dcjSSc and lcjSSc at time of inclusionWhole CohortN=175Diffuse SubtypeN=128Limited SubtypeN=47P valueFemale to Male Ratio4.3:1 (142/33)4.1:1 (103/25)4.8:1 (39/8)0.829Cutaneous subtypeDiffuse subtype73% (128)1280Limited subtype27% (47)047Mean Disease duration (years)3.1 (± 2.7)3.3 (± 2.9)2.6 (± 2.2)0.135Mean age of onset of Raynaud´s (years)10.0 (± 3.8)17 non-Raynaud9.8 (± 3.6)10 non-Raynaud10.6 (± 4.3)7 non-Raynaud0.219Mean age of onset of non-Raynaud´s (years)10.2 (± 3.9)10.0 (± 3.7)10.9 (± 4.3)0.173Disease modifying drugs88% (154)89% (114)85% (40)0.446CutaneousMean modified Rodnan skin score14.3 (0-51)17.4 (0-51)6.1 (0-24)0.001Gottron Papules27% (46/171)33% (41/124)11% (5)0.003Sclerodactyly78% (126/162)82% (98/119)65% (28/43)0.020Laboratory valuesElevated CK25% (30/122)30% (26/88)12% (4/34)0.041VascularTelangiectasia36% (56/154)44% (49/111)16% (7/43)0.001History of ulceration53% (91/173)61% (77/127)30% (14/46)0.001CardiacCardiac Involvement6% (10)2% (3)15% (7)0.002Patient Related OutcomesPhysician global disease activity(0-100) min -max35(0-90) n=14138(0-90) n=10825(0-80) n=330.002Physician global disease damage(0-100) min -max31(0-85) n=14034(0-85) n=10819(0-60) n=320.008Results from this large international cohort of jSSc patients demonstrate significant differences between dcjSSc and lcjSSc patients. According to the general organ involvement and physician global scores, the dcjSSc patients had significantly more severe disease. These observations strengthen our previous findings of the unique organ pattern of pediatric patients.Supported by the “Joachim Herz Stiftung”None declared.

Multisystem inflammatory syndrome in children (MIS-C) is a rare complication of SARS-CoV-2 infection in the pediatric population, caused by extensive activation of immune system. The understanding of the distorted immune response is still in the early stages.To analyze comprehensively immune profile in MIS-C patients including detailed serologic response to SARS-CoV-2 in comparison with control groups.Blood samples of consecutive MIS-C patients were collected at admission. Flow cytometric analysis of all lymphocyte populations including T and B cell differentiation was performed. Immunophenotyping was performed by six-color panels for the detection of lymphocyte subpopulations. Anti-SARS-CoV-2 specific antibodies were measured in the patients serum. The IgA and IgG antibodies against S protein, the IgG S1 and S2 specific antibodies, antibodies against nucleoprotein and neutralising antibodies were measured. Patients were assessed for a wide range of auto-antibodies, namely ANA, anti-ENA (Jo-1, PL-7, PL-12, SRP, Mi-2, Ku, Pm/Scl 100, Scl-70), myositis specific antibodies (EJ, MDA-5, TIH-Y, Ro52, SAE-1, SAE-2, NXP-2), anti-dsDNA, anti-phopholipid antibodies (aCl IgA, IgG, IgM, antiβ2GPI IgG, IgM) and ANCA. Control groups to compare specific antibody response consisted of 14 healthy children and 19 healthy adults, who had SARS-CoV-2 infection in the last 2 months.Samples of 20 patients were included (14/20 boys, median age 12.4 years). Patients had higher percentage of double negative T cells and low numbers of of cytokine producing T cells Th1, Th2 and Th17. . Numbers of immune competent and CD21+ transitional B cells were also lowered. All patients had positive antibodies against SARS-CoV-2 including neutralising antibodies. Nine (9/19; 47 %) patients had high titer (≥1:160) of neutralising antibodies. Results were compared with 2 control groups; 14 healthy children (7/14 boys; median age 8 years,) and 19 healthy adults, who all experienced SARS-CoV-2 infection in the last two months. Patients with MIS-C had significantly higher levels of anti-S IgA (p<0.0001), patients with MIS-C and healthy children had significantly higher titers of anti-S1 (p=0.001) and significantly lower titers of anti-S2 (p=0.016) in comparison to adults (Figure 1). No differences were found in the titers of neutralising antibodies and anti-N antibodies. All patients were ANA negative, 19/20 patients were anti-ENA negative, whereas 1 patient had anti-Ro antibodies in low titre. Three patients had aCL IgG in medium titre and 2 patients anti-beta2GPI IgG in low titre. Patients were negative for all other autoantibodies.The immune response in MIS-C patients is specific with most prominent differences in elevated percentage of double negative T cells and low numbers of Th1, Th2, Th17 and CD21+ transitional B cells. MIS-C patients have distinct serologic response with high anti-S IgA, high anti-S1 and low anti-S2 titres.Figure 1.Antibody titres in patient group and control groups. Mean value with SEM s shown.None declared.

A growing number of professional societies in clinical and medically related disciplines investigate evidence, make recommendations, and take action to advance gender equity. Evidence on women’s advancement and leadership in the context of the European Alliance of Associations for Rheumatology, EULAR, is limited [1].The objective of the EULAR Task Force on Gender Equity in Academic Rheumatology was to establish the extent of the unmet need for support of female rheumatologists, health professionals and non-clinical scientists in academic rheumatology and develop a framework to address this through EULAR and Emerging EULAR Network (EMEUNET).Potential interventions to accelerate gender-equitable career advancement in academic rheumatology were gathered from a narrative review of the relevant literature, expert opinion of a multi-disciplinary Task Force (comprised of 23 members from 11 countries), data from the surveys of EULAR scientific member society leaders, EULAR and EMEUNET members, and EULAR Executive Committee members. These interventions were rated by Task Force members, who ranked each according to perceived priority on a five-point numeric scale from 1 = very low to 5 = very high.A framework of 29 potential interventions was formulated, which covers six thematic areas, namely, EULAR policies, advocacy and communication, EULAR Congress and associated symposia, training courses, mentoring/peer support, and EULAR funding (Figure 1).Figure 1.A framework of potential interventions with the levels of priority, mean and standard deviation (SD)The framework provides structured interventions for accelerating gender-equitable career advancement in academic rheumatology.[1]Andreoli L, Ovseiko PV, Hassan N, et al. Gender equity in clinical practice, research and training: Where do we stand in rheumatology? Joint Bone Spine 2019;86(6):669-72.The task force is grateful to EULAR for funding this activity under project number EPI 024.None declared

Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated to a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans. Here we report four new patients carrying biallelic DNASE1L3 pathogenic variations, including two previously unreported mutations. Disease in one patient was characterized by lupus nephritis and skin lesions, while two others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented with early-onset inflammatory bowel disease. To explore whether or not the interferon cascade was strongly and sustainably induced, Interferon stimulated genes (ISGs) expression was assessed for each patient. Contrary to canonical type-I interferonopathies, we noticed a transient increase of ISGs in blood, which reverted to normal with disease remission. Reviewing previous reports, DNASE1L3-related disease appears to carry a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). DNASE1L3 deficiency may share the pathogenesis with C1q deficiency by affecting efferocytosis, and this report suggests that interferon production is not directly driven by DNASE1L3 pathogenic variants.

To evaluate the baseline clinical characteristics of juvenile systemic sclerosis (SSc) patients in the international juvenile SSc inception cohort, and to compare these characteristics between the classically defined juvenile diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) subtypes and among those with overlap features.

The American College of Rheumatology guidance for management of pediatric patients with multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 have been recently published. The guidance was prepared by the multidisciplinary Task Force and provide a very rational approach to management of this condition. There is, however, one area in which we are in disagreement.

During the COVID-19 pandemic, the need to provide high-level care for a large number of patients with COVID-19 has affected resourcing for, and limited the routine care of, all other conditions. The impact of this health emergency is particularly relevant in the rare connective tissue diseases (rCTDs) communities, as discussed in this Perspective article by the multi-stakeholder European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET). The clinical, organizational and health economic challenges faced by health-care providers, institutions, patients and their families during the SARS-CoV-2 outbreak have demonstrated the importance of ensuring continuity of care in the management of rCTDs, including adequate diagnostics and monitoring protocols, and highlighted the need for a structured emergency strategy. The vulnerability of patients with rCTDs needs to be taken into account when planning future health policies, in preparation for not only the post-COVID era, but also any possible new health emergencies. In this Perspective article, members of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases discuss clinical and organizational challenges in this community caused by the COVID-19 pandemic and what lessons might be learned for the future.

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.

Utilizing data obtained from a prospective, international, juvenile systemic sclerosis (SSc) cohort, the present study was undertaken to determine if pulmonary screening with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) is sufficient to assess the presence of interstitial lung disease (ILD) in comparison to high‐resolution computed tomography (HRCT) in juvenile SSc.