The first parent-child diagnosis of a multifocal squamous odontogenic tumor: A case report.

Squamous odontogenic tumors (SOT) are rare, benign, odontogenic neoplasms of the jaws. The sporadically reported cases with multifocal SOTs seem to have a marked predilection for younger African American patients. In this case report a 14-year-old Caucasian male presented with swelling of the vestibular alveolar process, slight tooth divergence, and mobility. A multifocal squamous odontogenic tumor was diagnosed and subsequently treated twice with surgical enucleation. Two and a half years earlier his mother was diagnosed and treated for a similar multifocal SOT. Next-Generation-Sequencing targeted resequencing mutational analysis of the maternal surgical specimens was performed. No potential causal mutation could be identified. Postoperative follow-up of the patient showed no recurrence of the SOT after 2 years. This case report substantiates the possibility of a familial relationship in (multifocal) SOT, possibly changing current ideas concerning the etiology and treatment of these neoplasms.

Factors affecting sports involvement in a school-based youth cohort: Implications for long-term athletic development.

The aim of the present study was to determine the factors affecting sports involvement in a school-based adolescent population. The cross-sectional cohort study assessed anthropometry, physical capacities and motor competence in 501 boys (aged 10-16 y), from junior (10-12 y) and senior (13-16 y) cohorts. Sports participation data was collected from junior participants. Multivariate analysis of covariance revealed moderate maturity, anthropometry, physical capacity and motor competence differences between sports in the senior cohort (F = 2.616, p < 0.001, η2 = .08), but not in the junior cohort. Furthermore, differences in physical fitness were revealed between playing levels (F = 2.616, p < 0.001, η2 = .08), with a discriminant analysis correctly classifying 73% of participants using aerobic fitness and vertical jump measures. Representative level participants engaged in more structured training and commenced organised competition at a later age (F = 4.332, p < 0.001, η2 = .21). This study's findings are twofold: 1) physical and motor competence profiles differ more between sports with increasing age, and 2) participants at a higher level of competition report delayed engagement in their main sport. As a result, schools may be the ideal environment in which to provide children and adolescents with the opportunity to sample different sports.

The use of the Körperkoordinationstest für Kinder in the talent pathway in youth athletes: A systematic review.

OBJECTIVES: Identifying talented athletes from an early age to accelerate their development requires the investment of substantial resources. Due to the need for multifactorial approaches to talent identification, motor competence assessments are increasingly prevalent in contemporary testing batteries. Therefore, the aim of this review was to evaluate the literature on the use of a product-oriented motor competence assessment tool, the Körperkoordinationstest für Kinder (KTK) in the talent pathway and determine whether it is warranted in such programs. METHODS: Three electronic databases (i.e. PubMed, SPORTDiscus and Web of Science) were searched for studies that used at least one component of the KTK to assess motor competence for talent detection, identification, development and selection in athletic populations. A total of 21 articles were included in the review, of which seven used the full version of the KTK and 14 used modified versions or individual components of the battery. The quality of included studies was assessed using a modified version of the Joanna Brigg's Institute Critical Appraisal Checklist. RESULTS: The analysed literature suggests that the KTK can successfully distinguish between athletes of different competition levels and across different sporting domains, however, findings should be interpreted with caution due to the cross-sectional nature of the studies. Furthermore, the moving sideways subtest displayed the greatest discriminative power for athletes of different competition levels. Motor competence was not affected by maturation and did not differ between genders or playing positions. CONCLUSIONS: Collectively, these findings suggest that the KTK is a useful motor competence assessment in the talent pathway.

qLessons learned from patients with access to an online self-management enhancing program for RA patients: Qualitative analysis of interviews alongside a randomized clinical trial.

OBJECTIVE: This study aims to explain the earlier findings of a Randomized Controlled Trial (RCT), which showed that rheumatoid arthritis (RA) patients did not benefit from an online self-management program. Moreover, less patients than expected used the program. METHODS: As part of an explorative RCT, patients were interviewed to explore their (non) usage of the program. Purposive sampling (n = 21) was used to select patients from four groups of patients (n = 49): 1) non-users; 2) low users; 3) high users basic; 4) high users plus. RESULTS: The program supported only a small group of patients because: 1) not all patients were motivated to use the program, 2) patients had no clear expectation or had differing expectations of the program, 3) there was a mismatch between individual patients' support needs and the needs included in the program, 4) reminders were only sent to fill in the diaries for pain and fatigue, not to use the program modules. CONCLUSION: This study offers insights in the (non-) usage of online programs and how usage could be increased in practice. PRACTICAL IMPLICATIONS: Health professionals should be involved in the implementation of this online programs and should inform patients what the program could bring them.

Intravenous cyclophosphamide pulse therapy in interstitial lung disease associated with systemic sclerosis in a retrospective open-label study: influence of the extent of inflammation on pulmonary function.

Interstitial lung disease (ILD) is the primary cause of death in patients with systemic sclerosis (SSc). It is thought that chronic inflammation is a key component in SSc-ILD. Treatment, such as cyclophosphamide (CYC), targets this inflammation. We hypothesized that treatment with CYC might be more effective in the inflammatory phase. Therefore, we analyzed whether the extent of inflammation, as assessed by the proportion of ground glass compared to fibrosis, SSc disease duration, the extent of ILD, or baseline diffusion capacity of the lungs (DLCO) < 60%, modifies the effect of intravenous CYC pulse therapy (750 mg/m2) on pulmonary function (as measured by FVC, DLCO) in SSc-ILD patients, after 12, 24, and 36 months. Consecutive patients with SSc-ILD receiving CYC pulses between 2003 and 2015 were included. Pulmonary function tests were performed at 0, 6, 12, 24, and 36 months. There were 75 patients included. Forced vital capacity (FVC) (86% of predicted) and DLCO (42% of predicted) were stable after 12, 24 and 36 months of follow-up (p > 0.05). Forty-four patients completed 12 cycles of CYC. For the extent of ILD, proportion of ground glass compared to fibrosis, SSc disease duration, and baseline DLCO, there were no differences (all p > 0.05) in the course of FVC and DLCO. Treatment with CYC followed by maintenance therapy stabilizes pulmonary function in patients with SSc-ILD over a 3-year period. The extent of ILD, proportion of ground glass, SSc disease duration, and baseline DLCO < 60% did not influence the effect of CYC on pulmonary function.

There is a need for new systemic sclerosis subset criteria. A content analytic approach.

OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted SCORE algorithms.

OBJECTIVES: Predictive performance of cardiovascular disease (CVD) risk calculators appears suboptimal in rheumatoid arthritis (RA). A disease-specific CVD risk algorithm may improve CVD risk prediction in RA. The objectives of this study are to adapt the Systematic COronary Risk Evaluation (SCORE) algorithm with determinants of CVD risk in RA and to assess the accuracy of CVD risk prediction calculated with the adapted SCORE algorithm. METHODS: Data from the Nijmegen early RA inception cohort were used. The primary outcome was first CVD events. The SCORE algorithm was recalibrated by reweighing included traditional CVD risk factors and adapted by adding other potential predictors of CVD. Predictive performance of the recalibrated and adapted SCORE algorithms was assessed and the adapted SCORE was externally validated. RESULTS: Of the 1016 included patients with RA, 103 patients experienced a CVD event. Discriminatory ability was comparable across the original, recalibrated and adapted SCORE algorithms. The Hosmer-Lemeshow test results indicated that all three algorithms provided poor model fit (p<0.05) for the Nijmegen and external validation cohort. The adapted SCORE algorithm mainly improves CVD risk estimation in non-event cases and does not show a clear advantage in reclassifying patients with RA who develop CVD (event cases) into more appropriate risk groups. CONCLUSIONS: This study demonstrates for the first time that adaptations of the SCORE algorithm do not provide sufficient improvement in risk prediction of future CVD in RA to serve as an appropriate alternative to the original SCORE. Risk assessment using the original SCORE algorithm may underestimate CVD risk in patients with RA.

The Yo-Yo intermittent recovery test level 1 is reliable in young high-level soccer players.

The aim of the study was to investigate test reliability of the Yo-Yo intermittent recovery test level 1 (YYIR1) in 36 high-level youth soccer players, aged between 13 and 18 years. Players were divided into three age groups (U15, U17 and U19) and completed three YYIR1 in three consecutive weeks. Pairwise comparisons were used to investigate test reliability (for distances and heart rate responses) using technical error (TE), coefficient of variation (CV), intra-class correlation (ICC) and limits of agreement (LOA) with Bland-Altman plots. The mean YYIR1 distances for the U15, U17 and U19 groups were 2024 ± 470 m, 2404 ± 347 m and 2547 ± 337 m, respectively. The results revealed that the TEs varied between 74 and 172 m, CVs between 3.0 and 7.5%, and ICCs between 0.87 and 0.95 across all age groups for the YYIR1 distance. For heart rate responses, the TEs varied between 1 and 6 bpm, CVs between 0.7 and 4.8%, and ICCs between 0.73 and 0.97. The small ratio LOA revealed that any two YYIR1 performances in one week will not differ by more than 9 to 28% due to measurement error. In summary, the YYIR1 performance and the physiological responses have proven to be highly reliable in a sample of Belgian high-level youth soccer players, aged between 13 and 18 years. The demonstrated high level of intermittent endurance capacity in all age groups may be used for comparison of other prospective young soccer players.

Effect of Aerobic Exercise Training on Fatigue in Rheumatoid Arthritis: A Meta-Analysis.

OBJECTIVE: Rheumatoid arthritis (RA) fatigue is not being well-managed currently, and evidence of effective interventions is limited. Aerobic exercise may provide benefit to treat fatigue in RA. Therefore, the purpose of this meta-analysis is to analyze the effect of aerobic land-based exercise on fatigue in RA. METHODS: A literature search was conducted using PubMed, Cochrane Library, Embase, and trial registers to identify randomized controlled trials (RCTs) with a supervised land-based aerobic exercise program performed with an intensity between 50% and 90% of maximal heart rate, of at least 15 minutes' duration, performed at least 2 times a week, and lasting for a time period of at least 4 consecutive weeks. Risk of bias was assessed using the Cochrane tool. A meta-analysis of fatigue outcomes was performed by calculating the standardized mean difference (SMD) using a random-effects model. RESULTS: Five RCTs were included. None of the trials selected patients with RA for having fatigue. Risk of bias was low in 3 RCTs and unclear in 2. Land-based aerobic exercise programs had a positive effect on fatigue in RA compared to no exercise at 12 weeks, SMD -0.31 (95% confidence interval [95% CI] -0.55, -0.06). At 24 weeks, the effect of aerobic land-based exercise was smaller and not statistically significant: SMD -0.15 (95% CI -0.33, 0.02). CONCLUSION: There is evidence with low risk of bias that an aerobic exercise program is effective in reducing fatigue among patients with RA, especially in the short term; however, effects are small. To substantiate the evidence, RCTs should be performed in patients with RA selected for having fatigue.

An increased risk of non-melanoma skin cancer during TNF-inhibitor treatment in psoriasis patients compared to rheumatoid arthritis patients probably relates to disease-related factors.

BACKGROUND: Concerns exist about a risk of non-melanoma skin cancer (NMSC) in psoriasis patients and rheumatoid arthritis (RA) patients treated with TNF-inhibitors. However, current data also show that in some psoriasis patients, NMSC is diagnosed relatively short after the start of TNF-inhibitors, which suggests that these NMSC can be explained by previous therapies instead of by TNF-inhibitor therapy. OBJECTIVE: To investigate whether there was a difference in time until first NMSC and the rate of NMSC between psoriasis and RA patients on TNF-inhibitors. METHODS: Time until first NMSC and the rate of NMSC were compared between psoriasis and RA patients from the same region treated with TNF-inhibitors and followed up for at least one year in prospective cohort studies, by using Cox regression and Poisson regression. Both analyses were corrected for confounders (age, gender, disease duration, prior NMSC, duration of anti-TNF and other systemic therapies). RESULTS: The NMSC risk was significantly higher in the psoriasis group [fully adjusted HR 6.0 (1.6-22.4 95%CI)] with a shorter time until first NMSC in psoriasis compared to RA. By Poisson regression, psoriasis patients had a 5.5 (2.2-13.4 95%CI) higher rate of NMSC. CONCLUSION: The time until first NMSC was significantly shorter and the rate of NMSC was significantly higher in psoriasis compared with RA. This indicates that disease-related factors like phototherapy may be important contributing factors to NMSC diagnosed in psoriasis patients treated with TNF-inhibitors.

Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis.

OBJECTIVE: This study was undertaken to assess the predictive ability of 4 established cardiovascular (CV) risk models for the 10-year risk of fatal and non-fatal CV diseases in European patients with rheumatoid arthritis. METHODS: Prospectively collected data from the Nijmegen early rheumatoid arthritis (RA) inception cohort was used. Discriminatory ability for CV risk prediction was estimated by the area under the receiver operating characteristic curve. Calibration was assessed by comparing the observed versus expected number of events using Hosmer-Lemeshov tests and calibration plots. Sensitivity and specificity were calculated for the cut-off values of 10% and 20% predicted risk. RESULTS: Areas under the receiver operating characteristic curve were 0.78-0.80, indicating moderate to good discrimination between patients with and without a CV event. The CV risk models Systematic Coronary Risk Evaluation (SCORE), Framingham risk score (FRS) and Reynolds risk score (RRS) primarily underestimated CV risk at low and middle observed risk levels, and mostly overestimated CV risk at higher observed risk levels. The QRisk II primarily overestimated observed CV risk. For the 10% and 20% cut-off values used as indicators for CV preventive treatment, sensitivity ranged from 68-87% and 40-65%, respectively and specificity ranged from 55-76% and 77-88%, respectively. Depending on the model, up to 32% of observed CV events occurred in patients with RA who were classified as low risk (<10%) for CV disease. CONCLUSIONS: Established risk models generally underestimate (Systematic Coronary Risk Evaluation score, Framingham Risk Score, Reynolds risk score) or overestimate (QRisk II) CV risk in patients with RA.

Relationship between objectively assessed physical activity and fatigue in patients with rheumatoid arthritis: inverse correlation of activity and fatigue.

OBJECTIVE: Fatigue is generally associated with low physical activity in patients with various chronic medical conditions. However, such an association has not been reported among patients with rheumatoid arthritis (RA). The objectives of this study were to investigate whether daily activity level is associated with fatigue in patients with RA, and whether pain, disability, coping, and/or cognition are associated with the level of daily activity. METHODS: Patients with RA who visited our outpatient clinic were recruited consecutively. Fatigue severity was measured using the Checklist Individual Strength (CIS20). Physical activity was measured for 14 consecutive days using an ankle-worn actometer. The daily activity level of each patient was calculated, and each patient was classified as having a low or high activity level with respect to the group average. Data were analyzed by linear regression. RESULTS: A total of 167 patients were included in the analysis; 25% had a low activity level and 75% had a high activity level. A regression analysis revealed that higher activity levels were associated with reduced fatigue (P = 0.008). The mean ± SD CIS fatigue score was 30.9 ± 12.3 among the patients with a high activity level and 35.7 ± 12.8 among the patients with a low activity level (P = 0.03). Pain, disability, coping, and cognition were not associated significantly with daily activity level. CONCLUSION: Among patients with RA, a higher level of daily physical activity was associated with reduced levels of fatigue. This relationship was not explained by differences in sex, age, disease duration, pain, disability, or other fatigue-related factors.

Association between fatigue and pain in rheumatoid arthritis: does pain precede fatigue or does fatigue precede pain?

OBJECTIVE: Fatigue and pain are important symptoms for patients with rheumatoid arthritis (RA), but their temporal association is unknown. Therefore, the objective of this study was to investigate the longitudinal relationship between fatigue and pain in patients with RA using time-lag models. METHODS: Consecutive RA outpatients (n = 228) were enrolled for this 1-year study. Fatigue was assessed monthly with the Checklist Individual Strength (CIS; range 8-56) and pain was assessed monthly with the bodily pain subscale (inverted, range 0-100) of the Short Form 36. The association between monthly changes in fatigue and pain was analyzed using longitudinal regression (mixed models), using the same months and with a 1-month time lag. RESULTS: A total of 198 patients were included in the analyses. At baseline, the mean ± SD pain score was 35.23 ± 19.82 and the mean ± SD CIS fatigue score was 31.0 ± 12.4. Severe fatigue at baseline (CIS score ≥35) was present in 42% of the patients. The mean ± SD patient-averaged CIS fatigue score over 1 year was 30.9 ± 6.0 and the mean ± SD patient-averaged pain score over 1 year was 36.4 ± 18.3. The longitudinal regression analysis showed a significant positive relationship between fatigue and pain during the same month (ß = 2.04; 95% confidence interval 1.82, 2.27). The models using a time lag showed no significant association between changes in pain and changes in fatigue. CONCLUSION: In established RA, pain and fatigue show monthly fluctuations that are synchronous rather than showing a temporal relationship with a time lag; within this timeframe, the results do not indicate that one precedes the other.

Relative age, biological maturation and anaerobic characteristics in elite youth soccer players.

Being relatively older and having an advanced biological maturation status have been associated with increased likelihood of selection in young elite soccer players. The aims of the study were to investigate the presence of a relative age effect (RAE) and the influence of birth quarter on anthropometry, biological maturity and anaerobic parameters in 374 elite Belgian youth soccer players. The sample was divided into 3 age groups, each subdivided into 4 birth quarters (BQ). Players had their APHV estimated and height, weight, SBJ, CMJ, sprint 5 and 30 m were assessed. Overall, more players were born in BQ1 (42.3%) compared with players born in BQ4 (13.7%). Further, MANCOVA revealed no differences in all parameters between the 4 BQ's, controlled for age and APHV. These results suggest that relatively youngest players can offset the RAE if they enter puberty earlier. Furthermore, the results demonstrated possible differences between BQ1 and BQ4, suggesting that caution is necessary when estimating differences between players because of large discrepancies between statistical and practical significance. These findings also show that coaches should develop realistic expectations of the physical abilities of younger players and these expectations should be made in the context of biological characteristics rather than chronological age-based standards.

The effect of anti-TNF-α vs. DMARDs on fatigue in rheumatoid arthritis patients.

OBJECTIVES: Fatigue is experienced frequently by patients with rheumatoid arthritis (RA). Fatigue may be caused by high levels of pain and disease activity in RA but can remain present while disease activity is moderate to low. It is not clear whether RA patients receiving anti-tumour necrosis factor (TNF) treatment reach lower levels of acute fatigue than RA patients receiving disease-modifying anti-rheumatic drug (DMARD) treatment. The aim of our study was to analyse whether, in patients with RA, the effect of anti-TNF on fatigue is greater than the effect of DMARD treatment. METHOD: Sixty-seven RA patients receiving anti-TNF treatment and 104 RA patients receiving DMARDs were included. All patients were on stable treatment for at least 6 months prior to baseline measurement. Fatigue was measured monthly over 1 year with the fatigue severity subscale of the Checklist Individual Strength (CIS-fatigue). The association between persistent severe fatigue and medication group was analysed using multiple linear regression including confounders. RESULTS: In the anti-TNF group the mean (SD) level of persistent fatigue was significantly higher than in the DMARD group [32.2 (11.4) vs. 28.3 (10.9), p = 0.025] and more patients experienced persistent severe (CIS-fatigue score ≥ 35) fatigue (42% and 27% respectively, p = 0.043). However, when correcting for age, disease activity, haemoglobin, treatment duration, pain, physical disability, and clinical depression, medication type seemed to influence neither the mean level of persistent fatigue (p = 0.251) nor the percentage of patients with persistent severe fatigue (p = 0.745). CONCLUSIONS: When taking into account probable confounders including disease activity, medication type did not influence persistent fatigue in RA patients. It seems that, besides its anti-inflammatory effect, anti-TNF has no complementary effect on persistent fatigue.

Functional consequences of sphingomyelinase-induced changes in erythrocyte membrane structure.

Inflammation enhances the secretion of sphingomyelinases (SMases). SMases catalyze the hydrolysis of sphingomyelin into phosphocholine and ceramide. In erythrocytes, ceramide formation leads to exposure of the removal signal phosphatidylserine (PS), creating a potential link between SMase activity and anemia of inflammation. Therefore, we studied the effects of SMase on various pathophysiologically relevant parameters of erythrocyte homeostasis. Time-lapse confocal microscopy revealed a SMase-induced transition from the discoid to a spherical shape, followed by PS exposure, and finally loss of cytoplasmic content. Also, SMase treatment resulted in ceramide-associated alterations in membrane-cytoskeleton interactions and membrane organization, including microdomain formation. Furthermore, we observed increases in membrane fragility, vesiculation and invagination, and large protein clusters. These changes were associated with enhanced erythrocyte retention in a spleen-mimicking model. Erythrocyte storage under blood bank conditions and during physiological aging increased the sensitivity to SMase. A low SMase activity already induced morphological and structural changes, demonstrating the potential of SMase to disturb erythrocyte homeostasis. Our analyses provide a comprehensive picture in which ceramide-induced changes in membrane microdomain organization disrupt the membrane-cytoskeleton interaction and membrane integrity, leading to vesiculation, reduced deformability, and finally loss of erythrocyte content. Understanding these processes is highly relevant for understanding anemia during chronic inflammation, especially in critically ill patients receiving blood transfusions.

Clinical prediction of 5-year survival in systemic sclerosis: validation of a simple prognostic model in EUSTAR centres.

OBJECTIVE: Systemic sclerosis (SSc) is associated with a significant reduction in life expectancy. A simple prognostic model to predict 5-year survival in SSc was developed in 1999 in 280 patients, but it has not been validated in other patients. The predictions of a prognostic model are usually less accurate in other patients, especially from other centres or countries. A study was undertaken to validate the prognostic model to predict 5-year survival in SSc in other centres throughout Europe. METHODS: A European multicentre cohort of patients with SSc diagnosed before 2002 was established. Patients with SSc according to the preliminary American College of Rheumatology classification criteria were eligible for the study when they were followed for at least 5 years or shorter if they died. The primary outcome was 5-year survival after diagnosis of SSc. The predefined prognostic model uses the following baseline variables: age, gender, presence of urine protein, erythrocyte sedimentation rate (ESR) and carbon monoxide diffusing capacity (DLCO). RESULTS: Data were available for 1049 patients, 119 (11%) of whom died within 5 years after diagnosis. Of the patients, 85% were female, the mean (SD) age at diagnosis was 50 (14) years and 30% were classified as having diffuse cutaneous SSc. The prognostic model with age (OR 1.03), male gender (OR 1.93), urine protein (OR 2.29), elevated ESR (1.89) and low DLCO (OR 1.94) had an area under the receiver operating characteristic curve of 0.78. Death occurred in 12 (2.2%) of 509 patients with no risk factors, 45 (13%) of 349 patients with one risk factor, 55 (33%) of 168 patients with two risk factors and 7 (30%) of 23 patients with three risk factors. CONCLUSION: A simple prognostic model using three disease factors to predict 5-year survival at diagnosis in SSc showed reasonable performance upon validation in a European multicentre study.

Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group.

OBJECTIVE: To identify a core set of preliminary items considered as important for the very early diagnosis of systemic sclerosis (SSc). METHODS: A list of items provided by European League Against Rheumatism (EULAR) Scleroderma Trial and Research(EUSTAR) centres were subjected to a Delphi exercise among 110 experts in the field of SSc. In round 1, experts were asked to choose the items they considered as the most important for the very early diagnosis of SSc. In round 2, experts were asked to reconsider the items accepted after the first stage. In round 3, the clinical relevance of selected items and their importance as measures that would lead to an early referral process were rated using appropriateness scores. RESULTS: Physicians from 85 EUSTAR centres participated in the study and provided an initial list of 121 items. After three Delphi rounds, the steering committee, with input from external experts, collapsed the 121 items into three domains containing seven items, developed as follows: skin domain (puffy fingers/puffy swollen digits turning into sclerodactily); vascular domain (Raynaud's phenomenon, abnormal capillaroscopy with scleroderma pattern) and laboratory domain (antinuclear, anticentromere and antitopoisomerase-I antibodies). Finally, the whole assembly of EUSTAR centres ratified with a majority vote the results in a final face-to-face meeting. CONCLUSION: The three Delphi rounds allowed us to identify the items considered by experts as necessary for the very early diagnosis of SSc. The validation of these items to establish diagnostic criteria is currently ongoing in a prospective observational cohort.