R. De Angelis

Predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis: a multicentre validation study

Introduction The early detection of systemic sclerosis (SSc) patients at high risk of developing digital ulcers could allow preventive treatment, with a reduction of morbidity and social costs. In 2009, a quantitative score, the capillaroscopic skin ulcer risk index (CSURI), calculated according to the formula ‘D×M/N2’, was proposed, which was highly predictive of the appearance of scleroderma digital ulcers within 3 months of capillaroscopic evaluation. Objectives This multicentre study aims to validate the predictive value and reproducibility of CSURI in a large population of SSc patients. Methods CSURI was analysed in 229 unselected SSc patients by nailfold videocapillaroscopy (NVC). All patients were re-evaluated 3 months later with regard to the persistence and/or appearance of new digital ulcers. Results 57 of 229 patients presented with digital ulcers after 3 months. The receiver operating characteristic curve analysis showed an area under the curve of 0.884 (95% CI 0.835 to 0.922), with specificity and sensitivity of 81.4% (95% CI 74.8 to 86.89) and 92.98% (95% CI 83.0 to 98.0), respectively, at the cut-off value of 2.96. The reproducibility of CSURI was validated on a random sample of 81 patients, with a κ-statistic measure of interrater agreement of 0.8514. Conclusions The role of CSURI was confirmed in detecting scleroderma patients with a significantly high risk of developing digital ulcers within the first 3 months from NVC evaluation. CSURI is the only method validated to predict the appearance of digital ulcers and its introduction into routine clinical practice might help optimise the therapeutic strategy of these harmful SSc complications.

Diffuse scleroderma occurring after the use of paclitaxel for ovarian cancer

Abstract A case of diffuse scleroderma in a 56-year-old woman who received paclitaxel for the treatment of a metastatic ovarian cancer is presented. The clinical cutaneous alterations, as well as the capillaroscopic and histological findings, were indistinguishable from those encountered in definite systemic sclerosis (SSc). In contrast to SSc, Raynauds phenomenon and cutaneous calcinosis were absent and antinuclear antibodies were negative. The temporal relationship between the onset of skin involvement and administration of the drug may indicate an effect of paclitaxel.

Clinical features of gout

Gout is a metabolic disease characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals in the joints and soft tissues, consisting of a self-limited acute phase characterized by recurrent attacks of synovitis and a chronic phase in which inflammatory and structural changes of the joints and periarticular tissues may lead to persistent symptoms. Acute gout is characterized by a sudden monoarthritis of rapid onset, with intense pain, mostly affecting the big toe (50% of initial attacks), the foot, ankle, midtarsal, knee, wrist, finger, and elbow. Acute flares also occur in periarticular structures, including bursae and tendons. The presence of characteristic MSU crystals in the joint fluid, appearing needle-like and showing strong negative birefringence by polarized microscopy, is pivotal to confirm the diagnosis of gout. The time interval separating the first attack from subsequent episodes of acute synovitis may be widely variable, ranging from a few days to several years. During the period between acute attacks the patient is asymptomatic even if MSU deposition may continue to increase silently. The factors that control the rate, location, and degree of ongoing deposition in gouty patients are not well defined. Chronic gout is the natural evolution of untreated hyperuricemia in patients with gouty attacks followed by pain-free intercritical periods. It is characterized by the deposition of solid MSU crystal aggregates in a variety of tissues including joints, bursae and tendons. Tophi can occur in a variety of locations including the helix of the ear, olecranon bursa, and over the interphalangeal joints. Their development is usually related with both the degree and the duration of hyperuricemia. About 20% of patients with gout have urinary tract stones and can develop an interstitial urate nephropathy. There is a strong association between hyperuricaemia and the metabolic syndrome (the constellation of insulin resistance, hypertension, obesity and dyslipidaemia), and gouty patients often have a medical history of kidney disease, diabetes mellitus and signs of vascular illness such as coronary artery disease, heart failure and stroke, resulting with a poor overall quality of life.

SAT0080 Patient Acceptable Symptom State (PASS) in Self-Report Questionnaires and Composite Clinical Disease Index for Assessing Rheumatoid Arthritis. Identification of Cut-Off Points for Routine Care: Table 1

Background In order to interpret better the patient-reported outcomes (PROs) score changes in clinical routine, some cut-points have been determined. One of these cut-points is the Patient-Acceptable Symptom State (PASS) that is defined as the highest level of symptom beyond which patients consider themselves well [1]. It is strictly a PRO, and consists of a global dichotomized simple question about patients satisfaction of their state of symptoms [2]. Objectives To provide information on the value of PASS in rheumatoid arthritis (RA) by the identification of PASS thresholds for PROs composite scores. Methods The characteristics of RA patients with affirmative and negative assignment to PASS were compared. Contributors to physician response were estimated by logistic regression models and PASS thresholds by the 75th percentile and receiver-operating characteristic (ROC) curve methods. Results 303 RA patients completed the study. All PROs were different between the PASS (+) and PASS (-) groups (p<0.0001). The thresholds with the 75th percentile approach were 2.0 for the RA Impact of Disease (RAID) score, 2.5 for the PRO-CLinical ARthritis Activity (PRO-CLARA) index, 1.0 for the Recent-Onset Arthritis Disability (ROAD) questionnaire and 3.3 for patients assessment of general health (Table). The cut-off values for Clinical Disease Activity Index (CDAI) were in the moderate range of disease activity. Assessing the size of the logistic regression coefficients, the strongest predictors of PASS were the disease activity (p=0.0007) and functional state level (0.006). Table 1 Variable PASS + 75th percentile threshold 80% Specificity cutoff ROC Cutoff Sensitivity/Specificity AUC-ROC curve ROAD (0–10) 1.00 1.10 1.50 92.7/60.1 0.788 PRO-CLARA (0–10) 2.50 2.60 2.90 89.1/82.7 0.933 RAID (0–10) 2.00 2.10 2.60 96.4/73.4 0.862 CDAI (0–76) 13.83 15.85 14.21 81.8/91.6 0.925 PASS thresholds for each specific patient-reported outcomes and other measures defined by the 75th percentile of the cumulative distribution, for patient who rated their condition as PASS-positive, by plotting ROC curves and identifying cutoffs that yielded 80% specificity and by plotting ROC curves and identifying cutoffs that yielded the smallest number of false-positives and false-negatives. Conclusions PASS thresholds were relatively high and many patients in PASS had moderate disease activity states according to CDAI. Factors such as disease activity and physical function may influence a negative PASS. References Kvien TK, Heiberg T, Hagen KB. Minimal clinically important improvement/difference (MCII/MCID) and patient acceptable symptom state (PASS): what do these concepts mean? Ann Rheum Dis 2007; 66(Suppl III): iii40-iii41. Tubach F, Ravaud P, Beaton D, et al. Minimal clinically important improvement and patient acceptable symptom state for subjective outcome measures in rheumatic disorders. J Rheumatol 2007; 34(5): 1188-93. Disclosure of Interest None declared

Systemic lupus erythematosus arthropathy: the sonographic perspective:

Background Despite being promising, the use of ultrasound (US) in the assessment of musculoskeletal manifestations of systemic lupus erythematosus (SLE) is still limited. Literature on this topic is scarce and the spectrum and clinical relevance of US abnormalities has not yet been outlined. With this paper, we aim to explore the panel of joint and tendon US findings in a group of SLE patients. Methods Twenty-five consecutive SLE patients, with current or medical history of musculoskeletal symptoms, were studied. All patients underwent routine clinical examination and US evaluation. The US examination targeted sites clinically involved in the physical examination and/or indicated as painful in the patient’s medical history. Results One or more US changes were found in all the patients. US abnormalities were detected in 85 out of the 243 scanned joints (35%), in 70 out of the 215 scanned tendons (32.6%) and in 10 out of the 41 scanned entheses (24.4%). Synovial effusion, synovial hypertrophy, “mixed” synovitis (coexistence of synovial effusion and synovial hypertrophy), joint dislocation, bone erosion, and cartilage damage were found in 9.5%, 11.5%, 14%, 3.7%, 2.1%, and 4.5% of the scanned joints, respectively. Tenosynovitis, tendon dislocation, tendon tear, tendon thinning, and tendinitis/peritendinitis were detected in 17.7%, 8.4%, 0.9%, 4.2%, and 4.7% of the scanned tendons, respectively. Power Doppler signal, hypoechogenicity, thickening, enthesophytes, calcifications, and bone erosions were detected at the entheseal level in 12.2%, 9.8%, 12.2%, 7.3%, 7.3%, and in 0% of the scanned entheses, respectively. Conclusions This study revealed an unexpectedly wide heterogeneity of US pathologic findings in the joints and tendons of patients with SLE. A broad spectrum of US changes also involving anatomic structures not considered in previous investigations, including entheses and tendons with no synovial sheath, was detected. These preliminary results suggest that US is able to identify several US “patterns” whose clinical, prognostic, and pathogenetic significance is still to be defined.

95 Efficacy, damage accrual and predictors of response to belimumab in active sle patients: a large italian multicenter prospective study

Background and aims To investigate effectiveness, damage accrual and predictors of response to belimumab in active SLE patients in clinical practice setting. Methods 188 active SLE patients with anti-dsDNA antibodies and low C3 and/or C4, from 11 Italian centres, were treated with belimumab as add-on-therapy. Gender, age, disease duration, polyarthritis, skin rashes, glomerulonephritis, haematological involvement, SLEDAI-2K≥10, prednisone ≥7,5 mg/day and concomitant immunosuppressants were used to determine baseline predictors of 12- and 24 month response according to SRI-4. Data were analysed by SPSS (version 22.0). Results Prominent clinical manifestations are summarised in Table 1. Clinical and serological variables at baseline, 12 and 24 months are reported in Table 2. SRI-4 was achieved by 71.3% and 68.7% of patients at 12 and 24 months, respectively. 92% of 12 month responders maintained SRI-4 response at 24 months; conversely, 87.5% of non-responders at 12 months were non-responders even at 24 months. Drug discontinuation for any cause was observed in 36.2% of patients; median treatment duration was 12 months. Damage accrual variation was significant between 5 years before drug initiation and baseline (p<0.001), but not between baseline and the end of follow-up (p=0.083). Baseline predictors of 12 month response were SLEDAI-2K≥10 (OR 25.8, 4.19–159.2) and polyarthritis (OR 8.33, 1.88–36.78); 24 month response predictors were SLEDAI-2K≥10 (OR 12.11, 1.63–89.80), polyarthritis (OR 32.56, 2.94–360.56), and prednisone dose ≥7.5 mg/day (OR 7.88, 1.02–61.48). Table 1 Refractory prominent clinical manifestation at baseline. Table 2 Disease features at baseline, 12 and 24 months (mean±SD). Conclusions Belimumab seems to be effective and to reduce damage accrual in SLE patients in clinical practice setting. Patients with arthritis and high disease activity were the best responders to belimumab.

AB0456 Safety and retention rate of belimumab: data from a multicentric italian study

Background Belimumab is used in the treatment of systemic lupus erithematosus (SLE), but few data on its safety in daily clinical practice are available to date. Objectives To investigate safety, retention rate (RR), reasons and predictors of belimumab discontinuation in a prospective multicentric Italian study. Methods A total of 188 active SLE patients refractory to standard therapy were treated with belimumab as add-on-therapy in 11 Italian centers. Adverse events (AEs) were defined as “any untoward medical occurrence in a patient treated with a pharmaceutical product which does not necessarily have a causal relationship with this treatment”. AEs were subdivided in non-infectious, infectious, infusion and hypersensitivity reactions. Infusion and hypersensitivity reactions were defined as transient AEs related to belimumab occurring within 6 hours and 6–48 hours after drug administration, respectively. AEs was defined as severe (SAE) in case of hospitalization and/or death and/or life-threatening manifestations. Infections were considered severe in case of hospitalization and/or intravenous antibiotic use and/or death. Infusion and hypersensitivity reactions were considered severe when intensive care unit support was required. As baseline predictors of discontinuation the following variables were analyzed: gender, age, age at SLE onset, disease duration, disease activity pattern (relapsing remitting or chronic active), SLEDAI-2K ≥10, prednisone >7.5 mg/day, concomitant immunosuppressant, antimalarial drug use, number and type of comorbidities, number of previous organ involvement, type of major involvement and number of flares in the 12 months before belimumab initiation. Data were analyzed using the SPSS (version 23.0, Chicago, IL) software. Results A total of 453 EAs were recorded in 132 patients after a mean follow-up period of 17.5±10.6 months (range 3–36): 443 (97.8%) were non severe and 10 (2.2%) SAEs (Table 1). No deaths and severe infusion/hypersensitivity reactions occurred. Belimumab discontinuation was observed in 58 patients (30.8%) after 10.4±7.5 months of follow-up (Table 2). RR was 91.5% at 6 months, 81.4% at 12 months, 72.9% at 18 months, 72.4% at 24 months, 69.7% at 30 months and 69.2% at 36 months. No associations were found between baseline variables and drug discontinuation. Conclusions Belimumab demonstrated a good safety profile with a low rate of SAEs. Discontinuation occurred in less than 1/3 of subjects with a low rate of discontinuation due to AEs. Disclosure of Interest None declared

FRI0297 A Quantitative Videocapillaroscopic Study about The Main Categories of The “Scleroderma Pattern” and Their Correlation with The Clinical Features of Systemic Sclerosis (SSC)

Background Many studies have been carried out in systemic sclerosis (SSc) in order to correlate the microvascular damage with the clinical features and/or organ involvement, most of them through qualitative assessment of the morphological abnormalities forming the so-called “scleroderma pattern” (SP). Quantitative studies about the SP are currently scarce, rarely addressing the relationship with the disease characteristics. Objectives To evaluate in a series of SSc patients the association between the types and extent of the SP with the clinical features and the disease severity. Methods Fifty-four patients (47 women and 7 men, mean age 59.5 years, median disease duration 13.0 years) consecutively enrolled, underwent nailfold videocapillaroscopy. For each patient, a total of 32 images were collected (4 images for the II, III, IV, V finger of both hands). All images were classified according to the following patterns: normal, non-specific, SP (with no reduction of the capillary density and with avascular areas). The patterns were correlated with such features as sex, age, disease duration, Raynauds phenomenon and/or digital ulcers (DU). Moreover, skin, muscle, gastrointestinal, pulmonary, heart and renal involvement were considered. Statistical analysis was performed using MedCalc version 12.0 (MedCalc Software, Mariakerke, Belgium). Results A total of 1728 images were analyzed and patients were divided into 4 subsets, on the basis of the extent of the SP. In subset 1 (6 patients, 11.2%) the extent was less than 25%, in subset 2 (5 patients, 9.2%) the extent was between 25–50%, in subset 3 (16 patients, 29.6%) between 50–75%, in subset 4 (27 patients, 50%) was more than 75%. Subsets 1 and 2 showed no significant relationship with any of the variables considered. Patients of subset 3 had a significant correlation with the presence of DU (p=0.007). The subset 4 showed a significant correlation with disease severity (p=0.03), history of DU (p=0.04) and the presence of DU (p≤0.0001). SP without reduction of the capillary density was correlated with the presence of lung fibrosis (p=0.04). The SP with avascular areas showed a significant relationship with disease severity (p=0.001), lung fibrosis (p=0.01), gastrointestinal involvement (p=0.01), skin involvement (p=0.03), history of DU (p=0.04), and DU (p=0.001). No association was found between patterns and disease duration. Conclusions The correlation observed between the presence of DU and/or history of DU both with the extent of the SP and the avascular areas represent a relevant data, confirming the hypothesis of a strong relationship between the fingertip blood perfusion and the integrity of the nailfold microvasculature. Unexpectedly, lung fibrosis showed a significant association both with the SP without reduction in capillary density and with the avascular areas. This fact leads us to consider the possibility of the multifactorial nature of pulmonary involvement, not only determined by a reduced number of capillaries. The lack of correlation between type and extent of the scleroderma pattern with the disease duration supports the concept that the severity of microangiopathy is not a characteristic of the late stages of the SSc. References De Angelis R, et al. A growing need for capillaroscopy in rheumatology. Arthritis Rheum 2009;61:405–10. Disclosure of Interest None declared

FRI0486 Health-Related Quality of Life in Systemic Sclerosis as Measured by SF-36, EQ-5D and SF-6D: Comparison with a Primary Raynaud Phenomenon and a Selected Sample of Healthy Controls

Background The health-related quality of life (HRQL) may be variously impaired in systemic sclerosis (SSc) and traditional methods of evaluation, with a focus on skin or musculoskeletal system, may fail to describe the extensive multi-dimensional issues associated to the disease. Objectives The aim of this study was to compare the HRQL scores of the Medical Outcome Study Short-Term 36 (SF-36) and of two widely used indirect utility instruments, the EuroQol-5D (EQ-5D) and the Short Form-6D (SF-6D), between SSc patients, subjects presenting only a primary Raynaud phenomenon (RP) and no other symptoms, and healthy controls. Methods A cross-sectional study was carried out among 417 patients (187 with SSc and 230 with primary RP) who were attending two academic outpatient clinics. SSc patients were further subdivided into two groups: patients with limited cutaneous SSc (lcSSc) (137 patients) and patients with diffuse cutaneous SSc (dcSSc) (50 patients), based on the distribution of the skin thickening and on the presence of autoantibodies. 582 healthy controls were used for the comparison. Patients were asked to complete SF-36, SF-6D and EQ-5D. SF-6D utility scores were calculated using the eight mean SF-36 scores, according to published algorithms. The following socio-demographic and clinical variables were included: age, gender, level of education and presence of comorbidities. Demographic and clinical measures were compared using Mann–Whitney U test or Kruskal-Wallis test for continuous variables, and chi-square analysis for discontinuous variables. Standardized difference scores (the s-score or normal score) were also calculated. Results In comparison to healthy controls, SSc patients showed a significant impairment in all of the eight subscales of the SF-36 (p<0.0001), as well as the physical and mental component summary scores (PCS and MCS) (p<0.0001), and in EQ-5D and SF-6D scores (p<0.0005).There were significant differences between dcSSc and lcSSc: dcSSC patients reported worse health in all SF-36 subscales, with particular emphasis on physical role, bodily pain and social function (p<0.0001) and on emotional role and mental health (p<0.001). Dimensions typically affected by SSc were general health status (s-score -1.47), bodily pain (s-score -1.21), physical function (s-score -0,80), social function (s-score -0,79), and physical role (s-score -0,73) whereas general health status (s-score -0.91), mental health (s-score -0,64) and bodily pain (s -score -0.55) were the only dimensions significantly impaired in primary RP patients. Conclusions HRQL of SSc patients was significantly impaired in contrast to primary RP and healthy controls, both in the SF36 physical and mental scores, as well as in EQ-5D and SF-6D scores. The significant differences found between dcSSc and lcSSc are to be emphasized, given the lack of literature on the subject. Further research is required to fully understand the respective role of the different evaluation methods and to examine the implications for estimates of the impact of health care interventions in SSc. References Gualtierotti R, Scalone L, Ingegnoli F, Cortesi P, Lubatti C, Zeni S, Meroni PL. Health related quality of life assessment in patients with systemic sclerosis. Reumatismo 2010; 62: 210-4. Disclosure of Interest None declared

FRI0584 Inter-Observer Agreement in the Quantitative Assessment of the Nailfold Capillaroscopic Findings in Systemic Sclerosis

Background Nailfold videocapillaroscopy (NVC) is a widely accepted technique used to assess microcirculation in patients with systemic sclerosis (SSc). However, very few studies have been focused in determining the variability of two different observers for the recognizing and scoring of the capillaroscopic findings by quantitative methods, as most of the authors has been working on qualitative and semi-quantitative evaluation. Objectives To investigate the inter-observer agreement in the quantitative assessment of the most relevant capillaroscopic abnormalities in patients with SSc. Methods Ten patients with diagnosis of SSc, according to the American College of Rheumatology criteria, were included in the study. All NVC examinations were performed blindly by two investigators with different experience in the field of NVC, at the second, third, fourth and fifth finger of both hands. Four consecutive images (one linear millimeter for each one) for all fingers were collected and stored, and the most visible was chosen. This image was examined to quantitatively assess the capillaroscopic parameters (number of dilated capillaries, total number of capillaries, number of microhaemorrhages, number of angiogenetic loops, and width of more dilated loop). The statistical analysis was made with MedCalc® version 12.4 (MedCalc software, Mariakerke, Belgium) for Widows XP. The inter-observer agreement was evaluated by weighted k (kw) for ordinal data (number of dilated capillaries, microhaemorrhages, and angiogenetic loops) and ICC-intraclass coefficient correlation (ICC) for quantitative data (number of loops and total width). Results A total of 84 consecutive images were evaluated. The overall number of the tracked and examined capillaries was 470. The kw values (95% CI) and the ICC (95% CI) for quantitative data were as follows: number of dilated capillaries 0.909 (0.829- 0.938); number of micro-haemorrhages 0.885 (0.715-0.991); number of angiogenetic loops 0.943 (0.912-0.967), number of total loops 0.992 (0.993-0.998); width of more dilated loop 0.991 (0.975-0.993). Good to excellent inter-observer agreement was present for all parameters. The recognition of the number of micro-haemorrhages was the parameter with a relatively lower degree of concordance. Conclusions Our data indicate a very good inter-observer agreement in the quantitative assessment of morphologic abnormalities by NVC in patients with SSc. This result demonstrate a high reproducibility of the capillaroscopy technique, which may be utilised in longitudinal studies to assess and quantify the microvascular damage, especially prior and after treatment with vasoactive drugs. References Gutierrez M, Bertolazzi C, Tardella M, Becciolini A, DI Carlo M, Dottori M, Grassi W, De Angelis R. Interreader reliability in assessment of nailfold capillary abnormalities by beginners: pilot study of an intensive videocapillaroscopy training program. J Rheumatol. 2012 Jun;39(6):1248-55. Disclosure of Interest None declared