Cardiac Intravoxel Incoherent Motion Diffusion-Weighted Magnetic Resonance Imaging With T1 Mapping to Assess Myocardial Perfusion and Fibrosis in Systemic Sclerosis: Association With Cardiac Events From a Prospective Cohort Study.

OBJECTIVE: Myocardial involvement may occur during systemic sclerosis (SSc) and can lead to impaired myocardial contraction and/or arrhythmia. Cardiac magnetic resonance imaging (MRI) is used for noninvasive characterization of the myocardium. The aim of this study was to evaluate the utility of cardiac MRI with intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and longitudinal relaxation time (T1) sequence mapping for assessment of myocardial microvascular and interstitium impairment in SSc. METHODS: In this single-center prospective cohort study, 40 consecutive patients with SSc and 20 healthy controls were assessed by cardiac MRI with IVIM DWI and T1 mapping sequences on a 3T scanning system. Images were analyzed independently by 2 assessors, and Bland-Altman plots were used to assess interreader concordance and reproducibility. Characteristics of the patients were compared according to quartiles of T1 and perfusion fraction (f-coefficient) values, using exact Cochran-Ermitage trend tests for qualitative variables and analysis of variance for quantitative variables. Kaplan-Meier cardiac events-free survival curves were plotted and compared with a log-rank test for trend. RESULTS: T1 values were higher in SSc patients than in healthy controls, and were higher in the diffuse cutaneous SSc (dcSSc) subset (P = 0.02). Higher T1 values were associated with the immunologic pattern seen in patients with the dcSSc form (P = 0.0001), a higher modified Rodnan skin thickness score (MRSS) (P = 0.003), and a higher frequency of interstitial lung disease (P = 0.03). Moreover, higher T1 values were correlated with higher MRSS scores (r = +0.32, P = 0.04) and reduced forced vital capacity (r = -0.34, P = 0.048), and tended to be correlated with reduced total lung capacity (r = -0.30, P = 0.07). Lower f-coefficient values, as a measure of decreased tissue perfusion, were associated with less frequent use of vasodilators (P = 0.02 for angiotensin-converting enzyme inhibitors and P = 0.06 for calcium-channel blockers) and more frequent use of glucocorticoids (P = 0.02). The f-coefficients were inversely correlated with the T1 values (r = -0.31, P = 0.02). Furthermore, higher T1 values were associated with higher incidence of cardiac events (log-rank test for trend P = 0.03). CONCLUSION: Increased T1 values, potentially suggesting microscopic fibrosis, were observed more frequently in patients with dcSSc, and higher T1 values were associated with interstitial lung disease and more frequent cardiac events during follow-up. The results of this study show that cardiac MRI with T1 mapping sequences and IVIM DWI may be useful in assessing myocardial involvement in patients with SSc.

State-of-the-art technologies provide new insights linking skin and blood vessel abnormalities in SSc-related disorders.

OBJECTIVE: A key unanswered question in systemic sclerosis (SSc) is how microvascular abnormality and fibrosis inter-relate. Our aim was to use state-of-the-art non-invasive imaging methods to gain new insights into pathophysiology, comparing patients with different subtypes of SSc, including early dcSSc, not only to healthy controls but also to patients with causes of Raynaud's phenomenon not progressing to fibrosis. METHODS: Laser Doppler imaging, nailfold capillaroscopy, spectroscopy, and ultrasound measured (respectively) perfusion, microvascular structure, oxygenation/oxidative stress, and skin thickening in the hands of 265 subjects: 31 patients with primary Raynaud's phenomenon (PRP), 35 with undifferentiated connective tissue disease (UCTD), 93 with limited cutaneous SSc (lcSSc), 46 with diffuse cutaneous SSc (dcSSc, including 27 'early') and 60 healthy controls. RESULTS: Mean perfusion was reduced in SSc groups compared to controls (lcSSc 172 perfusion units [standard deviation 157], late-dcSSc 90 [145], early-dcSSc 68 [137] vs. controls 211 [146]; p = 0.0002) as was finger-oxygenation (lcSSc 12.1 [13.6] arbitrary units [AU], late-dcSSc 12.2 [8.4], early-dcSSc 11.1 [11.3] vs controls 14.9 [10.5]; p = 0.0049). Oxidative stress was increased at the hand-dorsum in SSc groups (p = 0.0007). Perfusion positively correlated with oxygenation (r = 0.23, p < 0.001), and capillary density negatively with skin thickness (r = -0.26, p < 0.001). CONCLUSION: Our findings lend support to the hypothesis that in SSc, particularly early dcSSc, (but not in PRP or UCTD), reduced perfusion (together with structural microvascular abnormality) associates with reduced oxygenation, with oxidative stress and with skin thickening/fibrosis, most likely driving a vicious cycle which ultimately results in irreversible tissue injury. Findings in skin may mirror alterations in internal organs.

Prevalence and predictors of hand involvement in Thai patients with systemic sclerosis.

AIM: Data regarding the clinical and radiographic hand involvement in Asian patients with systemic sclerosis (SSc) are limited. Thus, we determined the prevalence of clinical and radiographic hand involvement in Thai SSc patients, comparing diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc). We also determined the factors associated with arthritis, contracture of fingers and digital ulcers. METHOD: SSc patients seen at the Rheumatology Clinic, Chiang Mai University, Thailand, from December 2012 to June 2013 were consecutively invited to enroll in the study. After study entry, demographic data, clinical features and hand radiographs were evaluated. RESULT: We studied 110 SSc patients (73 dcSSc) with mean ± SD age of 53.2 ± 9.2 years and disease duration from non-Raynaud's phenomenon of 4.9 ± 4.8 years. The prevalence of arthritis, finger contractures and digital ulcers were 10 (9.1%), 47 (42.7%), and 14 (12.7%), respectively. DcSSc patients had significantly more of the following hand complications than lcSSc patients: digital pitting scar (53.4% vs. 27.0%, P = 0.008), digital ulcer (17.8% vs. 2.7%, P = 0.032), traumatic ulcer (27.4% vs. 0%, P < 0.001), acrolysis (45.2% vs. 18.9%, P = 0.007) and flexion contracture (60.3% vs. 8.1%, P < 0.001). Radiographic finger contractures were more prevalent in the dcSSc subset. In multivariate logistic regression analysis, a positive rheumatoid factor was associated with arthritis; dcSSc, arthritis and modified Rodnan skin score (MRSS) > 18 were associated with contracture of fingers. Furthermore, hand MRSS > 4 was associated with digital ulcers. CONCLUSION: Our results confirm that dcSSc patients had more severe clinical hand complications than lcSSc. However, radiographic findings were similar among subgroups, except that more finger contractures were seen in dcSSc. Finally, the presence of rheumatoid factor is associated with arthritis, and high MRSS is associated with finger contractures and digital ulcers.

Subclinical dermal involvement is detectable by high frequency ultrasound even in patients with limited cutaneous systemic sclerosis.

BACKGROUND: The aim of the study was to detect by skin high-frequency ultrasound (US) possible subclinical skin involvement in patients affected by limited cutaneous systemic sclerosis (lcSSc), in those skin areas apparently not affected by the disease on the basis of a normal modified Rodnan skin score (mRSS). Differences in dermal thickness (DT) in comparison with healthy subjects were investigated. METHODS: Fifty patients with lcSSc (age 62 ± 13 years (mean ± SD), disease duration 5 ± 5 years) and 50 sex-matched and age-matched healthy subjects (age 62 ± 11 years) were enrolled. DT was evaluated by both mRSS and US at the usual 17 skin areas (zygoma, fingers, dorsum of the hands, forearms, upper arms, chest, abdomen, thighs, lower legs and feet). Non-parametric tests were used for the statistical analysis. RESULTS: Subclinical dermal involvement was detected by US even in the skin areas in patients with lcSSc, who had a normal local mRSS. In addition, statistically significantly higher mean DT was found in almost all skin areas, when compared to healthy subjects (p < 0.0001 for all areas). In particular, DT was significantly greater in patients with lcSSc than in healthy subjects in four out of six skin areas with a normal mRSS (score = 0) (upper arm, chest and abdomen), despite the clinical classification of lcSSc. CONCLUSIONS: This study strongly suggests that subclinical dermal involvement may be detectable by US even in skin areas with a normal mRSS in patients classified as having lcSSc. This should be taken into account during SSc subset classification in clinical studies/trials.

Nailfold Videocapillaroscopic Features and Other Clinical Risk Factors for Digital Ulcers in Systemic Sclerosis: A Multicenter, Prospective Cohort Study.

OBJECTIVE: To identify nailfold videocapillaroscopic features and other clinical risk factors for new digital ulcers (DUs) during a 6-month period in patients with systemic sclerosis (SSc). METHODS: In this multicenter, prospective, observational cohort study, the videoCAPillaroscopy (CAP) study, we evaluated 623 patients with SSc from 59 centers (14 countries). Patients were stratified into 2 groups: a DU history group and a no DU history group. At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and assessment of demographic characteristics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression (MLR) analyses. RESULTS: Of the 468 patients in the DU history group (mean ± SD age 54.0 ± 13.7 years), 79.5% were female, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow-up. The strongest risk factors for new DUs identified by MLR in the DU history group included the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs (categorized as 0, 1, 2, or ≥3), and the presence of critical digital ischemia. The receiver operating characteristic (ROC) of the area under the curve (AUC) of the final MLR model was 0.738 (95% confidence interval [95% CI] 0.681-0.795). Internal validation through bootstrap generated a ROC AUC of 0.633 (95% CI 0.510-0.756). CONCLUSION: This international prospective study, which included detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc, identified the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs at enrollment, and the presence of critical digital ischemia at enrollment as risk factors for the development of new DUs.

Pulmonary hypertension and interstitial lung disease within PHAROS: impact of extent of fibrosis and pulmonary physiology on cardiac haemodynamic parameters.

OBJECTIVES: We sought to examine the relationship between measures of ILD severity and PH in patients with SSc. METHODS: We identified 55 subjects from 12 PHAROS sites with RHC-proven PH and HRCT evidence of ILD. Subjects with PH due to left heart disease were excluded. Baseline HRCT scans were scored by a standardised system that graded severity of ILD. Summary statistics were generated for baseline characteristics. Spearman correlation and linear regression were used to examine relationships between ILD and PH severity variables. RESULTS: The majority of subjects were white women; nearly half had limited cutaneous SSc. Most subjects were New York Heart Association functional class II or III. Pulmonary function testing revealed moderate restriction (mean FVC 64.3 ± 17.2% predicted) with severe reduction in diffusing capacity (mean DLco 34.2 ± 13.3% predicted). RHC demonstrated mild to moderate PH (mean PAP 35 ± 9 mmHg, mean PVR 5.1 ± 3.7 WU). There was no correlation between severity of ILD (by either HRCT or PFT) and cardiac haemodynamic parameters of PH. CONCLUSIONS: No association between severity of ILD and cardiac haemodynamic profiles were identified in this cohort. We believe this underscores the complex nature of PH and ILD in individuals with SSc. We do suspect that some individuals with SSc-ILD will also have concomitant pulmonary vascular disease but simple assessments to grade severity of ILD - by PFT or HRCT estimates of ILD extent - are likely not enough to reliably distinguish between PAH versus PH-ILD. Further research into how to distinguish and manage these subsets is warranted.

Limited scleroderma with pauci-immune glomerulonephritis in the presence of renal cell carcinoma.

Connective tissue disorders increase the risk of malignancy; conversely, they may manifest as rheumatological paraneoplastic syndromes due to an underlying malignancy. We describe the case of a patient with limited scleroderma whose rapid disease progression coincided with the discovery of a renal tumor. A woman, age 75 years, presented with a 3-month history of progressive difficulty grasping objects, unsteadiness, dyspnea, xerostomia, xerophthalmia, and significant weight loss. She had a 10-year history of gastroesophageal reflux and Raynaud's phenomenon. Pertinent physical examination findings included facial telangiectasias, bibasilar inspiratory rales, sclerodactyly, and absent pinprick and vibratory sensation in her toes. She also had swelling and tenderness in several metacarpophalangeal and interphalangeal joints and in both ankles. A renal mass was demonstrated on abdominal computed tomography. A left partial nephrectomy was performed, confirming an unclassified type of renal cell carcinoma, along with a focal proliferative crescentic pauci-immune glomerulonephritis. Medical therapy with rituximab, pulse methylprednisolone, and prednisone led to improvement in her symptoms. The patient's presentation is consistent with a rapid progression of pre-existing limited scleroderma with the development of new rheumatological symptoms, including vasculitis. We propose that this progression was secondary to paraneoplastic stimulation by the renal cell carcinoma. Clinicians should consider looking for a malignancy in patients with connective tissue disorders who present with a myriad of new symptoms.

High-resolution computed tomographic findings in systemic sclerosis-associated interstitial lung disease: comparison between diffuse and limited systemic sclerosis.

OBJECTIVE: This study aimed to compare the high-resolution computed tomographic (HRCT) findings between patients with diffuse cutaneous systemic sclerosis (DcSSc) and limited cutaneous systemic sclerosis (LcSSc) as well as to correlate the HRCT scores and the other variables. METHODS: The medical records of all patients with SSc who presented at the Rheumatology Clinic, Chiang Mai University Hospital, from March 2005 to 2010 and underwent HRCT of the chest for the presence of interstitial lung disease were retrospectively reviewed. The extent of ground glass, lung fibrosis, and honeycombing was scored. All scores were aggregated to produce a total CT perfusion score. The widest coronal esophageal diameter (WED), the maximum diameter of the main pulmonary artery (MPAD), and ascending aortic diameter (AD) were measured. The ratio of MPAD to AD (MPAD/AD) was calculated. RESULTS: Of the 71 patients with SSc, mean (SD) age and disease duration were 54.8 (11.8) and 3.9 (4.2) years, respectively. Of them, 69.0% were female and 67.6% were classified as having DcSSc. There were no significant differences between patients with DcSSc and LcSSc with respect to age, disease duration, New York Heart Association Functional Classification, the calculated HRCT scores, WED, and MPAD. The lung fibrosis and total CT perfusion score correlated inversely with the SpO2 (r = -0.47, P < 0.01). The honeycombing correlated positively with the New York Heart Association Functional Classification and the WED (r = 0.29 and r = 0.32, respectively, P < 0.05). CONCLUSIONS: The HRCT scores of these patients were comparable in both subtypes of SSc. Careful evaluation of lungs and esophageal involvement should be performed irrespective of SSc subtypes. The calculated HRCT scores may be useful to assess the severity of the interstitial lung disease in SSc.

Reactivity of pulmonary circulation and right ventricle function to inhaled nitric oxide in systemic sclerosis patients.

Systemic sclerosis (SSc) is complicated by pulmonary hypertension and right ventricle (RV) failure in approximately 10% of the patients. Factors influencing the reactivity of pulmonary circulation to vasodilators are not established, while the examination of vasoreactivity is important in determining the treatment, because systemic administration of oral vasodilators can induce severe adverse events in nonresponders. The mechanism of RV failure in SSc is unclear and may result either from increased RV afterload or intrinsic myocardial disease. The aim of the study was to assess the reactivity of pulmonary circulation to inhaled nitric oxide (iNO) and to evaluate its influence on RV function in SSc patients with elevated right ventricle systolic pressure (RVSP). In 60 SSc patients aged 24-73 (58 females, two males; 33 patients with limited SSc and 27 with diffuse SSc), echocardiographic examination with tissue Doppler echocardiography (TDE) was performed. RV function was measured by systolic (S) and early diastolic (E) velocity of tricuspid annulus by TDE. In patients with RVSP >45 mmHg, the reactivity of pulmonary circulation was assessed by iNO test. High-resolution computerized tomography (HRCT) was performed to assess the extent of pulmonary fibrosis. Of 14 SSc subjects with elevated RVSP (13 females, one male; RVSP 47-62 mmHg), positive reaction to iNO was observed in five (RVSP decreased from 51.6 ± 3.7 to 32.24 ± 2.3 mmHg); nine patients were not reactive (RVSP 53.5 ± 5.7 mmHg before iNO vs. 49.6 ± 6.7 mmHg). RV systolic function was decreased in patients with elevated RVSP as compared to the patients with normal pulmonary pressure (S velocity 13.2 ± 1.3 vs. 14.4 ± 1.6 cm/s, respectively, p < 0.05). Significant increase of RV systolic function during iNO test was found in reactive patients only (S velocity before iNO 12.8 ± 1.2 cm/s, during iNO 14.5 ± 1.5 cm/s, p < 0.01). RVSP decrease strongly correlated with S velocity increase (r = 0.95, p < 0.0001). Response to iNO was found only in limited form of SSc; diffuse SSc patients showed no response. Pulmonary fibrosis on HRCT was more frequent in subjects nonreactive to iNO (67% of patients) than in the reactive group (40% of patients). The reactivity of pulmonary circulation to iNO in SSc patients with elevated RVSP was found predominantly in limited form of the disease. Pulmonary fibrosis typical for diffuse SSc was more frequent in nonreactive subjects. Elevated pulmonary pressure plays an important role in RV systolic dysfunction. Pulmonary pressure decrease during iNO test leads to the improvement of RV systolic function. Therapy for right-heart failure in reactive SSc patients should be directed, if possible, at the decrease in pulmonary resistance.

Early detection of median nerve syndrome at the carpal tunnel with high-resolution 18 MHz ultrasonography in systemic sclerosis patients.

OBJECTIVES: To investigate carpal tunnel syndrome (CTS) with ultrasound (US) in asymptomatic SSc patients and to seek out the relationship between CTS and SSc clinical variables METHODS: In 64 SSc patients (55 women and 9 men, mean age 57±14 years) and in 30 healthy controls, area (MNA), transverse (MNT) and anteroposterior (MNAP) diameters of MN at carpal tunnel were studied with US (My Lab 25 XVG US Esaote 18 MHz). MN flattening ratio (MNFR) was calculated. Duration of disease, subset (limited, diffuse), phase of skin involvement (oedematous, atrophic, fibrotic), modified Rodnan skin score (mRSS) and friction tendon rub were also recorded. RESULTS: MNA (p<0.001), MNT (p<0.005) and MNFR (p<0.005) were significantly higher in the SSc patients than in controls, while no difference in MNAP was found. There was no correlation between median nerve (MN) and SSc clinical features (only lower MNAP correlated inversely with longer disease duration; Spearman coefficient -0.2). CONCLUSIONS: MN involvement is frequently present in all phases of asymptomatic SSc patients, independently to clinical variables.

Endothelial function and hemodynamics in systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is characterized by the development of fibrosis of skin and internal organs that is associated with vascular damage. However, its related parameters have not been fully explored. The aim of this study was to investigate endothelial function in SSc and its relationship with systolic pulmonary artery pressure and systemic arterial compliance (SAC). METHODS: We studied 14 SSc females (4 with diffuse and 10 with limited cutaneous form of the disease) and 14 healthy controls matched for age and for cardiovascular risk factors. Endothelium-dependent dilation (i.e. flow-mediated) and endothelium-independent (i.e. nitroglycerin-induced) dilation of the brachial artery were measured as the percentage of change from baseline (FMD and NMD, respectively). In patients with SSc, SAC, cardiac output (CO), systemic arterial resistance and pulmonary artery pressure were estimated using echocardiography Doppler. RESULTS: Heart rate, brachial artery pressure and body mass index did not differ between patients with SSc and controls. Flow-mediated vasodilation (FMD) and NMD were significantly decreased in patients with SSc (10.3 ± 8.6 versus 26.6 ± 7.4%, P<0.001; 24.2 ± 8.4 versus 33.3 ± 10.1%, P<0.001, respectively). Postischaemia reactive hyperaemia was lower in patients with SSc (275 ± 185 versus 618 ± 366%, P<0.001). FMD and nitrate-mediated dilation (NMD) were associated with CO, but not with SAC; moreover, FMD correlated with pulmonary artery pressure and peripheral arterial resistance conversely to NMD. CONCLUSIONS: Endothelium function in SSc is impaired independently to SAC. Furthermore, the severity of both small artery and pulmonary artery involvement may impact on endothelium-dependent function.

Ultrasound elastography assessment of skin involvement in systemic sclerosis: lights and shadows.

OBJECTIVE: To assess skin elasticity in systemic sclerosis (SSc) by using a new imaging modality, ultrasound elastography (UE). METHODS: Our study included 18 consecutive patients with SSc and 15 healthy controls. Modified Rodnan skin score, physical examination, and assessment of organ involvement were performed. UE was carried out on the middle forearm and on the fingers of the dominant arm. The echo signals recorded in real time during freehand operations of probe compression and relaxation produced images representing tissue elasticity, consisting of translucent colored bands superimposed on the B-mode ultrasonographic images. The color scale varied within a large band spectrum from red, indicative of soft and highly elastic tissue, to blue, which denoted hard and barely elastic tissue. RESULTS: On the forearm of all patients, UE showed a homogeneous blue area corresponding to the dermis visualized in a B-mode ultrasonographic image; in controls, a blue pattern was never detected and a predominance of green with sporadic areas of pale blue was observed. At sequential evaluations, UE of fingers produced inconstant and changeable colored areas. CONCLUSION: The imaging pattern observed in the forearm of patients with SSc may represent the reduction of strain in the dermis due to loss of elasticity. The variable pattern obtained by finger evaluation demonstrated that UE can assess skin involvement in SSc only in those areas where the dermis is known to be thicker and where the bone hyperreflection is minimal. Further studies are needed to confirm our results and determine the validity of this new imaging modality.