Francesca Braschi

Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions

OBJECTIVE To evaluate in SSc, the frequency of digital lesions and the morphology, characteristics, natural course and time to healing of 1614 digital ulcers (DUs). METHODS One hundred SSc patients were followed up for 4 years. In the first step, the digital lesions were observed and classified at the time of presentation [digital pitting scar (DPS); DU; calcinosis; gangrene]. In the second step, DUs were divided into subsets according to their origin and main features. In the third step, the time to healing was recorded for each DU and the influence of DU main characteristics on time to healing was also evaluated. RESULTS In the first step, 1614 digital lesions were observed: DPS, 712 (44.1%) lesions; DU, 785 (48.6%); calcinosis, 110 (6.8%); and gangrene, 7 (0.8%). In the second step, DUs were subsetted as follows: DU developed on DPS (8.8%), pure DU; DU developed on calcinosis (60%); DU derived from gangrene. In the third step, the mean time to healing was 25.6 (15.6) days in DPS, 76.2 (64) days in pure DU, 93.6 (59.2) days in calcinosis ulcers and 281.1 (263.3) in gangrene. CONCLUSIONS In SSc, digital lesions are represented by DPS, DU, calcinosis and gangrene, and provide an evidence-based DU subsetting according to their origin and main characteristics. Subsetting may be helpful for a precise DU evaluation and staging, and in randomized controlled trials for a precise identification of those DUs that are to be included in therapeutic studies.

Autologous mesenchymal stem cells foster revascularization of ischemic limbs in systemic sclerosis: a case report.

BACKGROUND Mesenchymal stem cells can differentiate into endothelial cells and participate in angiogenesis in adults. In experimental models of acute myocardial infarction, mesenchymal stem cells led to the recovery of cardiac function through the formation of a new vascular network. OBJECTIVE To describe treatment with intravenous infusions of expanded autologous mesenchymal stem cells in 1 patient with critical limb ischemia due to systemic sclerosis. DESIGN Case report. SETTING The rheumatology unit at the University of Florence, Florence, Italy. PATIENT A woman, aged 34 years, with systemic sclerosis who developed acute gangrene of the upper and lower limbs. INTERVENTION 3 intravenous pulses of expanded autologous mesenchymal stem cells. MEASUREMENTS Angiography, skin histopathology, and immunohistochemistry. RESULTS Areas of necrotic skin were reduced after the first mesenchymal stem-cell infusion. After the third infusion, angiography showed revascularization of the patients extremities. Skin section analysis revealed cell clusters with tubelike structures, and angiogenic factors were strongly expressed. LIMITATION Causality cannot be established by a single case. CONCLUSION In patients with systemic sclerosis who have severe peripheral ischemia, intravenous infusion of expanded autologous mesenchymal stem cells may foster the recovery of the vascular network, restore blood flow, and reduce skin necrosis. PRIMARY FUNDING SOURCE Fondazione Cassa di Risparmio di Pistoia e Pescia (partial funding).

Digital ulcers as a sentinel sign for early internal organ involvement in very early systemic sclerosis

OBJECTIVE The aim of this study was to evaluate the presence of digital lesions in very early diagnosis of SSc (VEDOSS) patients and its possible association with internal organ involvement. METHODS One hundred and ten VEDOSS patients were investigated for the presence of digital ulcers (DUs), digital pitting scars, calcinosis, necrosis or gangrene, nailfold videocapillaroscopic abnormalities, disease-specific autoantibodies (ACA and anti-topo I) and internal organ involvement. RESULTS Four patients reported a history of digital pitting scars, while 25 patients presented an active DU or reported a history of DUs. In particular, 16 patients presented with active DUs (14/16 also reporting a history of previous DUs), while the other 9 patients reported a history of DUs only. A statistically significant association between DUs and oesophageal manometry alteration was found in the whole DU population, as well as in the history of DU and the presence of active DU with/without a history of DU subgroups (P < 0.01, P = 0.01 and P < 0.05, respectively). DUs were observed in VEDOSS patients with internal organ involvement but not in those without organ involvement. CONCLUSION DUs are already present in VEDOSS patients characterized by internal organ involvement, significantly correlating and associating with gastrointestinal involvement. DUs may be a sentinel sign for early organ involvement in VEDOSS patients.

Assessment, Definition, and Classification of Lower Limb Ulcers in Systemic Sclerosis: A Challenge for the Rheumatologist

Objective. To evaluate pathogenesis and clinical features of lower limb ulcers in systemic sclerosis (SSc) and to propose a classification that could be used in clinical practice. Methods. Charts of 60 patients with SSc who had lower limb cutaneous lesions were reviewed. All patients had videocapillaroscopy and arterial and venous lower limb color Doppler ultrasonography (US). Arteriography was performed if occlusive peripheral arterial disease was suspected. Results. The 554 lesions were classified as hyperkeratosis, ulcers, and gangrenes. There were 341 (61.6%) hyperkeratoses, 208 (37.5%) ulcers, and 5 (0.9%) gangrenes. Ulcers were divided into pure ulcers, ulcers associated with hyperkeratosis, and ulcers secondary to calcinosis. Involvement of arterial and venous macrocirculation as determined by color Doppler US was observed in 17 (18.3%) and 18 (30%) patients, respectively. Seventeen out of 37 patients with pure ulcers (45.9%) presented neither venous insufficiency nor hemodynamically significant macrovascular arterial disease. In these patients, pure ulcers were most likely caused by isolated SSc-related microvascular involvement (pure microvascular ulcers). The only significant risk factor for development of pure microvascular ulcers in the multivariate analysis was the history of lower limb ulcers (OR 26.67, 95% CI 2.75–259.28; p < 0.001). Conclusion. Results of our study indicate that lower limb ulcers in SSc often have a multifactorial pathogenesis that may be difficult to manage. Further studies are needed to validate the proposed classification and to assess the most appropriate management of lower limb ulcers in SSc.

Calcinosis in systemic sclerosis: subsets, distribution and complications

OBJECTIVE To retrospectively analyse the features of calcinosis in a cohort of SSc patients. METHODS Charts of SSc patients attending the Ulcer Unit of the Rheumatology Department, University of Florence and presenting a clinical suspicion of calcinosis were considered in the study. Data on clinical history, including recent skin changes, and clinical examination of all areas with suspected calcinosis, radiological imaging of the calcinotic area, demographics and SSc-related organ involvement and pain measured by a visual analogue scale were recorded. RESULTS In 52 of 112 SSc patients, a total of 316 calcinoses were recorded and were divided into visible and palpable {154 [47.4%], clustered according to their macroscopic features as mousse [49 (31.8%)] and stone [: 105 (68.2%)]} and non-visible but palpable {: 162 [52.6%]: net [5 (3%)], plate [22 (13.8%)] and stone [135 (83.2%)]}. The X-ray-based classification of all calcinoses, both visible and non-visible, was as follows: stone, 289 (91.4%); net, 12 (3.8%) and plate, 15 (4.8%). Skin ulcers complicated 154 of 316 calcinoses (48.7%). Mousse calcinosis was associated with pulmonary arterial hypertension, the stone subset was suggestive of pulmonary involvement and justified further investigation and the net subset was the slowest to heal. CONCLUSION Our data indicate that calcinosis may be classified in SSc as mousse, stone, net and plate according to its clinical and X-ray features. This classification awaits validation for a possible use in clinical practice and to support early treatment and prevention of complications.

District disability, fatigue and mood disorders as determinants of health related quality of life in patients with systemic sclerosis.

Joint Bone Spine - In Press.Proof corrected by the author Available online since samedi 11 octobre 2014

FRI0372 The ducas: proposal for a digital ulcer assessment score in scleroderma

Background No objective measure is presently available to assess digital ulcer (DU) in SSc patients apart from “healed/non healed” and experience-based clinical judgment. Objectives The aim of the current study is to propose a composite DU clinical assessment score (DUCAS) and, to lend it, test its face validity by correlating it with commonly used disease related patient-reported outcomes (PROs) and physician evaluation. Methods SSc patients presenting at least one DU and attending the Rheumatology Wound Care Clinic of the Florence University Hospital or the London Royal Free Hospital were enrolled. Patients were assessed with HAQ-DI, Cochin scale, Visual analogic scale (VAS) for DU-related pain (DU_pain, 0–100 mm), patient VAS for global DU status (ptGDU, 0–100mm) and patient global assessment (PtGA, 0–100 mm) as PROs and physician VAS for DU status (phyGDU, 0–100mm). The DUCAS included 7 DU related variables selected by a committee of 8 SSc DU experts - they are outlined in figure 1. Each variable was weighted on a clinical basis and the DUCAS score was the sum of the values for the 7 variables (max=19.5). Spearmans correlation tests were calculated for to examine face validity. A linear regression model with forward and backward stepwise analysis was used to determine the relationship of individual variables with the primary clinical parameter, phyGDU. Results 44 SSc patients (9 males, mean age 54,3±15,6 years, mean disease duration 9,9±5,8 years) were enrolled in the study. Mean phyGDU was 44,3±23mm, mean ptGDU was 54±30mm (Wilcoxon p=0.022, phyGDU VAS vs ptGDU) and mean DUCAS score was 4,2±2. Overall DUCAS showed significant positive correlations with all PROs, but when all the individual clinician and patients variables were modelled, only the overall DUCAS significantly predicted PhyGDU; after backwards stepwise analysis overall DUCAS and ptGDU best predicted PhyGDU, with an adjusted R2=0,437 and AIC=380,3 (Table 2).Table 1 A Linear Regression for DUCAS B Linear Model to PhyGDU Linear Model to PhyGDU after backwards stepwise Spearman Correlation p Estimate SE p Estimate SE p PtGA 0,56 <0,001 PtGA 0,011 0,199 0,955 PtGDU 0,54 <0,001 PtGDU 0,171 0,233 0,467 0,272 0,101 0,01 DU_Pain 0,44 0,003 DU_Pain 0,048 0,182 0,793 HAQ-DI 0,44 0,003 HAQ-DI 4,58 7,563 0,549 COCHIN 0,51 <0,001 COCHIN 0,035 0,252 0,891 PhyGDU 0,63 <0,001 DUCAS 4,636 1,617 0,007 4,841 1,489 0,002 Conclusions DUCAS is a newly proposed clinical score for SSc related DU which has face validity and which may reflect DU status as judged by SSc experts. Further validation of this score will be undertaken. Acknowledgements Cosimo Bruni received a EULAR travel bursary to run this project in the UK. Disclosure of Interest None declared

AB0591 Nailfold Videocapillaroscopy May Not Reflect Change of Digital Ulcers Status in A Short Term Evaluation of Systemic Sclerosis Patients

Background Nailfold videocapillaroscopy (NVC) is a useful tool in systemic sclerosis (SSc) patients, useful not only for the diagnosis but also to predict the development of organ and vascular complications, such as the utility of the recently proposed semi-quantitative scoring for digital ulcers (DU) [1]. Objectives to prospectively evaluate the change of prevalence of NVC microvascular alterations and their possible correlations with changes in patients-reported outcomes (PROs) and clinical-reported outcomes (CROs) and prevalence of clinical characteristics related to DU in SSc patients. Methods SSc patients presenting at least one DU and attending the Rheumatology Wound Care Clinic of the Florence University Hospital or the London Royal Free Hospital were enrolled. Patients were assessed with PROs (HAQ-DI, UKFS, Cochin scale, VAS for pain, DU status and general disease status) and CROs (VAS for DU status) at baseline and after 16 weeks. DU number, appearance of new DU, presence of gangrene, infection, need for hospitalization or surgery procedures, painkillers use were recorded at each visit. NVC was performed at both visit and the presence of micro-haemorrhages, giant capillaries, irregularly enlarged capillaries, ramified capillaries, capillary disorganization and loss of capillaries was scored according to the previously proposed score (0 = no changes, 1 = from 0 to 33%; 2 = from 33% to 66%, 3 = more than 66%). Correlations were tested through Spearman test. Results twenty-five SSc patients were eligible for the study. No significant correlation was seen at baseline; when analysing changes between baseline and follow-up, a negative correlation was seen between irregularly enlarged capillaries and the majority of PROs; moreover, changes of number of DU showed negative correlation with changes of giant capillaries, possibly reflecting the evolution of microvascular damage. Conclusions NVC is useful tool to predicting DU development, but may not reflect short term change in DU status; therefore a longer-term evaluation may be necessary to detect NVC modifications paralleling DU changes in SSc patients. References Smith V., Pizzorni C., De Keyser F, et al. “Validation of the qualitative and semiquantitative assessment of the scleroderma spectrum patterns by nailfold videocapillaroscopy: preliminary results,” Arthritis and Rheumatism, vol. 60, pp. S164–S165, 2009. Disclosure of Interest None declared

SAT0219 Correlation between Patient-Reported Outcomes and Changes in Digital Ulcer Status in Systemic Sclerosis Patients

Background Among various measures used to evaluate patients with systemic sclerosis (SSc), the Health Assessment Questionnaire (HAQ-DI) for disability, the UK scleroderma Functional Score (UKFS) and the Cochin Scale for hand functionality, the Visual Analogic Scale (VAS) to estimate pain, general disease activity and digital ulcers status are among the more frequently used [1]. Digital Ulcers (DU) are a major clinical complication in patients with Systemic Sclerosis (SSc), leading to a severe impairment of the quality of life and possibly determining important complication (from infections to amputation). Objectives this study aimed at evaluating the correlation between Clinician-Reported outcomes (CROs) and patient-reported outcome (PROs) and how changes in different parameters related to DU status in SSc patients may reflect changes in the above mentioned outcome measures. Methods SSc patients presenting at least one DU and attending the Rheumatology Wound Care Clinic of the Florence University Hospital or the London Royal Free Hospital were eligible for the study. Patients were assessed with HAD-DI, UKFS, Cochin scale, VAS for pain, DU status and general disease status (as PROs) and VAS for DU status (as CROs) at baseline and then every 4 weeks for a total of 16 weeks (or until DU healing, if occurred before). Number of DU, appearance of new DU, presence of gangrene, infection, need for hospitalization or surgery procedures, painkillers use were recorded at each visit. Correlations were tested through Spearman test. Results forty-four SSc patients were enrolled in the study. At baseline, all the PROs and CROs were positively correlated to each other, with most of the scales being also correlated with baseline DU number, presence of infection, need for hospitalization and painkillers use. When investigating baseline to mean follow-up changes, significant correlations were confirmed between CROs and PROs (except for VAS for general disease status), as well as between changes in PROs/CROs and changes of DU parameters being already significant at baseline. Conclusions PROs are useful outcome measures paralleling changes in clinical evaluation of DU status, which is influenced by changes in DU number, presence of infection, need for hospitalization and painkillers use. References Pope J. Measures of systemic sclerosis (scleroderma): Health AssessmentQuestionnaire (HAQ) and Scleroderma HAQ (SHAQ), physician- and patient-ratedglobal assessments, Symptom Burden Index (SBI), University of California, LosAngeles, Scleroderma Clinical Trials Consortium Gastrointestinal Scale (UCLA SCTCGIT) 2.0, Baseline Dyspnea Index (BDI) and Transition Dyspnea Index (TDI) (Mahlers Index), Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR), and Raynauds Condition Score (RCS). Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11:S98–111. Disclosure of Interest None declared

FRI0395 Digital ulcers as a “sentinel” sign for early internal organ involvement in very early systemic sclerosis: evidence from a single vedoss/eustar centre.

Objectives Evaluation of the presence of digital lesions [1] in patients with diagnosis of very early systemic sclerosis (VEDOSS) [2] and of their correlation with clinical, laboratory and imaging parameters. Methods 110 VEDOSS patients were investigated for presence of digital pitting scar, calcinosis, digital ulcers (DUs), necrosis or gangrene, nailfold videocapillaroscopic abnormalities, disease specific autoantibodies (anti-centromere and anti-topoisomerase I) and internal organ involvement (chest HRCT, pulmonary function tests with DLCO evaluation, oesophagealmanometry, Holter ECG, cardiac Doppler US, renal arteries Doppler US) [3]. Results 4 patients reported a history of digital pitting scars, 16 patients presented active DU and 14/16 also reported a history of previous DUs. Other 9 patients reported a history of DUs only. Both the history and the presence of DUs showed statistically significant correlation with esophageal manometry only (analyzed through IBM SPSS Statistics version 19, using Spearman’s Rho test:ρ=0,681 &ρ=0,633 respectively, p < 0,05). Clustering patients according to the presence of internal organ involvement, DUs were observed in VEDOSS patients with internal organ involvementbut not in those without organ involvement. Image/graph Conclusions DUs are already present in VEDOSS patients and correlate with esophageal involvement [4]. DU may be considered as a sentinel sign for the presence of early organ involvement, meaning the evolution from thevery early to the early phase of systemic sclerosis [5]. References Amanzi L et al. Digital ulcers in scleroderma:staging, characteristics and sub-setting through observation of 1614 digital lesions. Rheumatology (Oxford).2010 ;49:1374-82. Avouac J et al, “Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group”, Ann Rheum Dis. 2011 Mar;70:476-81. Czirjak L, Matucci Cerinic M: Beyond Raynaud’s phenomenon hides a very early systemic sclerosis: the assessment of organ involvement is always mandatory. Rheumatology 2011;50:250-1 Lepri G et al: Evidence for Esophageal and anorectal involvement in patients with very early diagnosis of systemic sclerosis (VEDOSS):report from a single EUSTAR centre. (Submitted) Matucci Cerinic M et al: Very early versus early disease: the evolving definition of the many faces of Systemic Sclerosis Ann Rheum Dis; 2012 Nov 23 Disclosure of Interest: None Declared