Joanne Manning

Noninvasive imaging techniques in the assessment of scleroderma spectrum disorders

OBJECTIVE Systemic sclerosis (SSc) affects both microvascular structure and function. Laser Doppler imaging (LDI) and thermal imaging can be used to measure cutaneous blood vessel function. Nailfold capillaroscopy (NC) measures capillary morphology. The aim of this study was to investigate the relationship between capillary morphology and blood flow, and to determine which combination of techniques allows the best discrimination between patients with SSc, primary Raynauds phenomenon (RP), and healthy controls. METHODS NC was performed in 16 patients with SSc, 14 patients with primary RP, and 16 healthy controls. In addition, participants underwent cold stimulus with cold water. Hands were imaged to monitor rewarming and reperfusion. Nailfold morphologic features were measured and baseline images and rewarming curves were analyzed. RESULTS Significant differences were found between groups (analysis of variance) for capillary morphologic features and rewarming curve characteristics. A correlation (P < 0.001) was found between LDI and thermal imaging at baseline (0.667) and maximum (0.729) blood flow and skin temperature, and for the areas under the rewarming curves (0.684). Receiver operating characteristic curves indicated that NC, thermal imaging, and LDI allowed 89%, 74%, and 72%, respectively, of SSc patient data to be correctly classified versus primary RP patients and controls. CONCLUSION NC, LDI, and thermal imaging each independently provide good discrimination between patients with SSc and those with primary RP and healthy controls (NC being the most suitable technique for classifying patient groups). However, a combination of all 3 techniques improves classification. LDI and thermal imaging give equivalent information on dynamic changes in the cutaneous microcirculation; however, these only weakly correspond to capillary morphology.

A multicentre study on the reliability of qualitative and quantitative nail-fold videocapillaroscopy assessment

OBJECTIVE To investigate the inter- and intra-observer reliability of both qualitative and quantitative parameters used in the assessment of nail-fold capillaroscopy images. METHODS Fifty mosaic nail-fold images of healthy controls (n = 10), patients with primary RP (n = 10) and SSc (n = 30) were assessed in random order by two blinded observers on two occasions at centres in Sweden, UK and The Netherlands. Each image was therefore scored by six observers twice. RESULTS Inter- and intra-observer reliability of quantitative parameters showed substantial to almost perfect agreement [inter- and intra-observer weighted κs for the number of widened capillaries was 0.75 and 0.87 and giant capillaries was 0.84 and 0.92, intra-class correlation coefficients (ICCs) for capillary density was 0.87 and 0.92 and total loop width was 0.94 and 0.98, respectively]. Qualitative parameters including architecture, avascularity, haemorrhage, crossed, ramified and bushy capillaries showed moderate to substantial inter-observer reproducibility (weighted κ ranging from 0.47 to 0.73), and substantial intra-observer repeatability (weighted κ ranging from 0.71 to 0.80), whereas the scoring of tortuous and bizarre capillaries showed poor inter-observer and substantial intra-observer agreement (inter-observer weighted κs was 0.39 and 0.21 and intra-observer weighted κs was 0.68 and 0.76, respectively). CONCLUSION All quantitative and certain qualitative parameters are highly reliable in terms of inter- and intra-observer agreement. A combination of parameters with the highest reliability should be incorporated into future capillaroscopic scoring systems in studies of prediction and monitoring of SSc spectrum disorders.

Thumb involvement in Raynaud's Phenomenon as an indicator of underlying connective tissue disease.

Objective. To conduct a retrospective study to assess whether the degree of thumb involvement differs between primary Raynaud’s phenomenon (PRP) and secondary Raynaud’s phenomenon (SRP). Methods. Thermography images from all patients attending Salford Royal Hospital and referred for thermography for assessment of RP between 2004 and 2006 were retrospectively reviewed. A distal dorsal difference (DDD) of −1°C or less between the fingertips and dorsum of the hand (fingers cooler) at 23°C was considered clinically relevant. The worse score (the lower score, i.e., the more negative value) from each pair of digits was considered for analysis. Results. One hundred seventy patients fulfilled the study criteria. DDD at 23°C for the thumbs were significantly higher (digital tips warmer) compared with other digits (p < 0.001) in both PRP and SRP. All digits were significantly warmer in PRP compared to SRP with the exception of the thumbs. The proportion of patients with clinically relevant involvement of thumbs was significantly higher in SRP compared to PRP (p = 0.003) and this difference was more pronounced in the thumbs compared with other digits. Conclusion. Although the median temperature gradient along the thumb was not significantly different between SRP and PRP, the thumb is more likely to be involved in SRP than in PRP. Thumb involvement is one of a number of clinical indicators that should alert the clinician to the possibility of an underlying connective tissue disease/disorder.

The influence of measurement location on reliability of quantitative nailfold videocapillaroscopy in patients with SSc

OBJECTIVES Nailfold videocapillaroscopy is being increasingly used as a marker of SSc-related microvascular disease, including in response to treatment. However, it requires further validation. Our aim was to assess the inter-observer, intra-observer and test-retest variability of semi-automated measurement of capillary features as well as of a manual density measurement. METHODS All capillary apexes in images from 58 patients with SSc were marked up independently by two trained observers (inter-observer variability). The first observer then re-marked the images (intra-observer variability), and finally, the first observer marked up a second image of the same nailfold (test-retest). Mark-up of capillaries was carried out on cropped mosaic images (cropped independently by the observers to a fixed width, to allow the same length of nail bed to be studied for each patient) and on whole mosaic images (examining the whole nail bed). RESULTS Reproducibility of independently cropped mosaic images was poor and was due to the variation in the positioning of the cropped area. However, quantification of whole mosaic images was highly reproducible, e.g. for inter-capillary distance, the intra-class correlation coefficient for inter-observer, intra-observer and test-retest reliability was 0.95, 0.98 and 0.90 (compared with 0.88, 0.79 and 0.89 for cropped mosaic images), respectively. Intra-observer limits of agreement for whole mosaic images were better than inter-observer reproducibility. CONCLUSION Quantitative assessment of SSc-related change in nailfold capillaries is unreliable if examination of the same set of capillaries cannot be guaranteed. Conversely a wide-field, high-magnification system that allows visualization of the whole nail bed offers a highly reproducible approach for quantitative assessment and therefore has potential as an outcome measure.

Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate

Objectives In patients with systemic sclerosis (SSc), fingertip digital ulcers (DUs) are believed to be ischaemic, and extensor surface DUs a result of mechanical factors/microtrauma. Our aim was to assess blood flow response to topical glyceryl trinitrate (GTN) compared to placebo in SSc DUs, looking for differences in pathophysiology between fingertip and extensor lesions. Method This was a double-blind, randomised, crossover, placebo-controlled study. Sixteen (6 fingertip, 10 extensor) DUs were each studied twice (one day apart): once with GTN and once with placebo ointment. Perfusion at the DU centre (‘DUCore’) and periphery (‘DUPeriphery’), as measured by laser Doppler imaging was performed before and immediately after ointment application, then every 10 min, up to 90 min post-application. We calculated the area under the response curve (AUC) and the ratio of peak perfusion to baseline, then compared these between GTN and placebo. Results Perfusion was lower in the DUCore compared to the DUPeriphery (ratio of 0.52). The microvessels of the DUCore were responsive to GTN, with an increase in perfusion, with a similar effect in both fingertip and extensor DUs. The AUC and peak/baseline perfusion difference in means (ratio, 95% confidence interval) between GTN and placebo at the DUCore were 1.2 (1.0–1.6) and 1.2 (1.0–1.5) respectively, and at the DUPeriphery were 1.1 (0.8–1.6) and 1.0 (0.9–1.2) respectively. Conclusion DUs (both fingertip and extensor) were responsive to topical GTN, with an increase in perfusion to the ischaemic DU centre. If both fingertip and extensor DUs have a (potentially reversible) ischaemic aetiology, this has important treatment implications.

Noninvasive Measurement of Skin Autofluorescence Is Increased in Patients with Systemic Sclerosis: An Indicator of Increased Advanced Glycation Endproducts?

Objective. Skin autofluorescence noninvasively assesses expression of advanced glycation endproducts and therefore potentially the presence of oxidative stress that is implicated in the pathogenesis of systemic sclerosis (SSc). We investigated whether autofluorescence was increased in patients with SSc, primary Raynaud’s phenomenon (RP), and morphea as compared to healthy controls. Methods. Measurements of autofluorescence were made at 5 upper limb sites in 16 healthy controls, 16 patients with diffuse cutaneous SSc (dcSSc), 15 with limited cutaneous SSc (lcSSc), 15 with primary RP, and 13 with morphea. For patients with morphea, additional measurements were made at the affected and an adjacent unaffected site. Results. Autofluorescence was significantly increased in patients with dcSSc but not lcSSc as compared to controls at the proximal phalanx [dcSSc median 0.15, interquartile range (IQR) 0.10–0.24, vs control 0.10, IQR 0.07–0.13; p = 0.014], dorsum of the hand (dcSSc 0.17, IQR 0.11–0.36, vs control 0.12, IQR 0.09–0.17; p = 0.031), the wrist (dcSSc 0.22, IQR 0.13–0.33, vs control 0.13, IQR 0.09–0.18; p = 0.005), and forearm (dcSSc 0.19, IQR 0.12–0.47, vs control 0.14, IQR 0.10–0.16; p = 0.022). There was a trend for autofluorescence to be increased in patients with lcSSc and at morphea sites, compared to noninvolved skin. Conclusion. Autofluorescence is increased in patients with dcSSc compared to primary RP and to healthy controls. This suggests increased oxidative stress and the potential for autofluorescence as a biomarker.

Thermographic Abnormalities are Associated with Future Digital Ulcers and Death in Patients with Systemic Sclerosis

Objective. Capillaroscopic abnormalities are predictive of future digital ulcers (DU). Our aim was to investigate whether functional digital vascular disease (thermographically assessed) is also associated with future DU. Methods. A retrospective case note review of patients with systemic sclerosis (SSc) undergoing thermography and who were followed for up to about 3 years. Results. There were 138 patients (equal mixture of normal/abnormal thermography). Patients with abnormal thermography were more likely to develop DU (clinician-observed and/or patient-reported, OR 2.84, p = 0.021), including multiple episodes, and more likely to die (OR 5.42, p = 0.050). Conclusion. Abnormal thermography is associated with DU and disease severity in patients with SSc.

A Multicenter Study of the Validity and Reliability of Responses to Hand Cold Challenge as Measured by Laser Speckle Contrast Imaging and Thermography: Outcome Measures for Systemic Sclerosis–Related Raynaud's Phenomenon

Reliable and objective outcome measures to facilitate clinical trials of novel treatments for systemic sclerosis (SSc)–related Raynauds phenomenon (RP) are badly needed. Laser speckle contrast imaging (LSCI) and thermography are noninvasive measures of perfusion that have shown excellent potential. This multicenter study was undertaken to determine the reliability and validity of a hand cold challenge protocol using LSCI, standard thermography, and low‐cost cell phone/mobile phone thermography (henceforth referred to as mobile thermography) in patients with SSc‐related RP.

Calcinosis preferentially affects the thumb compared to other fingers in patients with systemic sclerosis

Objectives: Although Raynaud’s phenomenon often spares the thumb, clinical experience suggests conversely that, in patients with systemic sclerosis (SSc), the thumb is frequently affected by calcinosis (as is demonstrated on plain radiographs). Our aim was to investigate the hypothesis that, in patients with SSc, thumbs are more commonly affected by calcinosis than other digits. Method: Sixty-eight hand radiographs with at least one area of calcinosis were identified. Each digit on both hands of each patient was assigned a severity score on a scale from 0 to 3 (0 = no calcinosis, 3 = most severe). The scoring was completed twice, including and excluding the metacarpals. Results: Right hands were found to be associated with slightly higher scores than left hands [estimate 0.14, 95% confidence interval (CI) 0.03–0.26]. Scores were lower for other fingers compared to thumbs. There was strong evidence (p < 0.0001) of a trend of decreasing severity moving from the thumb to the little finger. There was no evidence that the pattern of severity across the fingers was different on left and right hands (p = 0.77). The results were similar whether or not metacarpals were included. Conclusions: The thumb is affected by calcinosis more than other digits, followed by the index finger. This observation provides insight into the pathogenesis of SSc-related calcinosis, which may relate more to repetitive trauma than to ischaemia.

A longitudinal study of ankle brachial pressure indices in a cohort of patients with systemic sclerosis

OBJECTIVES Digital ischaemia, often progressing beyond RP to digital ulceration and sometimes even gangrene, is the most common vascular manifestation of SSc. Both microvascular and macrovascular disease can contribute and coexistence of microvascular and macrovascular (proximal vessel) disease in patients with SSc is potentially limb threatening. The aims of this study were to examine the change over time in the ankle brachial pressure index (ABPI) in a cohort of patients with SSc and to examine whether age, gender, smoking status, disease duration, disease subtype and ACA are associated with ABPI. METHODS The clinical and laboratory data of 217 patients attending the SSc clinic at a tertiary referral centre and who had their ABPIs checked between 1996 and 2011 were reviewed retrospectively. Data were analysed to see how the ABPI changed with time and linear mixed effects modelling was used to determine which factors were associated with ABPI. RESULTS In most patients with SSc, the ABPI remained constant over time [median rate of change 0 units/year, interquartile range (IQR) -0.01-0.01]. There was a significant association between lower ABPI and increasing age (P = 0.04), the limited cutaneous subtype of SSc (P = 0.01) and ACA positivity (P = 0.03). Additionally there was an association between ABPI and smoking status of borderline statistical significance (P = 0.08). CONCLUSION This study provides further evidence for associations between the severity of vascular disease in patients with SSc and increasing age, smoking, limited cutaneous disease and positive ACA. Reassuringly, in most patients ABPI remains stable over time.