Polarisation-sensitive optical coherence tomography measurement of retardance in fibrosis, a non-invasive biomarker in patients with systemic sclerosis.

Polarisation-sensitive optical coherence tomography (PS-OCT) offers a novel, non-invasive method of assessing skin fibrosis in the multisystem disease systemic sclerosis (SSc) by measuring collagen retardance. This study aimed to assess retardance as a biomarker in SSc. Thirty-one patients with SSc and 27 healthy controls (HC) underwent PS-OCT imaging. 'Skin score' was assessed by clinical palpation (0-3 scale). A subset of ten patients and ten age/sex-matched HC had a biopsy and longitudinal imaging. Histological assessment included quantification of epidermal thickness, collagen content (to assess fibrosis) and matrix metalloproteinase (MMP) activity (in situ zymography). PS-OCT images were assessed for epidermal thickness (structure) and fibrosis (retardance). Positive correlation was observed between epidermal thickness as measured by histology and structural PS-OCT (r = 0.79; p < 0.001). Retardance was: HC mean 0.21 (SD 0.21) radian/pixel; SSc skin score 0, 0.30 (0.19); skin score 1, 0.11 (0.16); skin score 2, 0.06 (0.12); skin score 3, 0.36 (0.35). Longitudinal retardance decreased at one-week across groups, increasing at one-month for HC/skin score 0-1; HC biopsy site retardance suggests scarring is akin to fibrosis. Relationships identified between retardance with both biopsy and skin score data indicate that retardance warrants further investigation as a suitable biomarker for SSc-related fibrosis.

Temperature response to cold challenge and mobile phone thermography as outcome measures for systemic sclerosis-related Raynaud's phenomenon.

Objectives: Objective outcome measures of systemic sclerosis (SSc)-related Raynaud's phenomenon (RP) are badly needed. Our objectives were to validate the thermographic response to a standard hand cold challenge as an outcome measure by assessing sensitivity to change, and to explore mobile phone thermography as a feasible, ambulatory tool.Method: Twelve patients with an SSc-spectrum disorder admitted for intravenous iloprost infusions underwent a standard cold challenge before and after one infusion. Thermographic measurements included area under the rewarming curve (AUC) and maximum rewarming temperature (MAX). Before and during another infusion, each patient underwent monitoring of finger skin temperature by two methods: continuous thermocouple recording (standard method) and mobile phone thermography.Results: All cold challenge summary measures, including AUC and MAX, increased after iloprost (most not significantly). However, when the response curves were modelled after averaging across fingers (linear mixed models, three versions), significant change was detected. For example, with Model 1 (no interaction between period and time), temperature was on average 1.67ºC [95% confidence interval (CI) 1.49-1.85, p < 0.001] higher post-iloprost. Mobile phone and thermocouple temperature measurements showed a strong estimated latent correlation (0.88, 95% CI 0.81-0.92). The estimated increases/hour were 0.25ºC (95% CI 0.05-0.45) for the thermocouple and 0.36ºC (95% CI 0.13-0.60) for mobile phone thermography.Conclusion: Our pilot study suggests that the thermographic response to a cold challenge is sensitive to change and mobile phone thermography could bring feasibility to thermographic parameters as outcome measures in later-phase, large-scale, community-based clinical trials of RP.

Imaging digital arteries in systemic sclerosis by tomographic 3-dimensional ultrasound.

Objective methods are needed to quantify digital artery disease in systemic sclerosis (SSc) for clinical trials of vascular therapies. Our primary aim was to examine feasibility of a novel tomographic three-dimensional-(3-D) ultrasound (tUS) with high-frequency ultrasound (HFUS) or ultra-high-frequency ultrasound (UHFUS) to assess the digital arteries in patients with SSc compared to healthy controls. A secondary objective was to compare the total wall volume (TWV) as a measure of intimal/medial thickness. Eighteen patients with a confirmed diagnosis of SSc were studied by tUS HFUS (17.5 MHz, n = 10) or tUS UHFUS (48 and 70 MHz, n = 8) with equal numbers of healthy controls of similar age and gender. The majority of patients had limited cutaneous SSc and were representative of a spectrum of digital vasculopathy, with over half (n = 6 HFUS and n = 5 UHFUS) having previous digital ulceration. Over half were receiving oral vasodilatory therapy. TWV was measured in both digital arteries of the middle finger bilaterally. At least, two digital arteries could be identified at 17.5 MHz in all patients and healthy controls. Whereas, at least two digital arteries could be identified in relatively fewer patients compared to healthy controls using 48 MHz (n = 6 and 10) and especially 70 MHz (n = 4 and 10) UHFUS. The median difference in TWV between patients and healthy controls was -6.49 mm3 using 17.5 MHz, 1.9 mm3 at 48 MHz, and -0.4 mm3 at 70 MHz. tUS using UHFUS is a feasible method to measure TWV of digital arteries in SSc. Transducer frequency plays an important factor in successful digital artery measurement, with 48 MHz being the optimal frequency.

Changes in disability and their relationship with skin thickening, in diffuse and limited cutaneous systemic sclerosis: a retrospective cohort study.

OBJECTIVE: The burden of disability associated with systemic sclerosis (SSc) is being increasingly recognized. Our aim was to test the hypothesis that changes in functional ability over time differ between patients with limited (lcSSc) and diffuse cutaneous (dcSSc) subtypes, and that in dcSSc (but not lcSSc) these changes correlate with skin thickening. METHOD: This was a retrospective analysis of data collected prospectively between 2005 and 2016 at a single centre. Data recorded at annual review visits included modified Rodnan skin score (mRSS) and Health Assessment Questionnaire Disability Index (HAQ-DI). Yearly rates of mRSS and HAQ-DI change were assessed by individual linear regressions, and those gradients were compared between disease groups (lcSSc/dcSSc) for each of early/late disease (less/greater than 5 years' duration). RESULTS: The study included 402 patients (110 dcSSc, 292 lcSSc), with mean length of follow-up of 5.5 years (sd 3.5). Mean baseline HAQ-DI was 1.4 in dcSSc and 1.2 in lcSSc. In dcSSc, increased mRSS was associated with worsening disability (ρ = 0.36, p = 0.004) during early but not late disease (ρ = 0.12, p = 0.331). In lcSSc, changes in mRSS were not associated with changes in disability for early (ρ = -0.15, p = 0.173) or late disease (ρ = 0.10, p = 0.137). CONCLUSION: These findings confirm high disability in patients with SSc. A relationship between HAQ-DI and mRSS (worsening mRSS associated with increasing disability) was found only in patients with early dcSSc, suggesting that in other patient subgroups other factors play the major role.

A feasibility study of a novel low-level light therapy for digital ulcers in systemic sclerosis.

BACKGROUND: Locally acting, well-tolerated treatments for systemic sclerosis (SSc) digital ulcers (DUs) are needed. OBJECTIVES: Our primary aim was to investigate the safety, feasibility, and tolerability of a novel low-level light therapy (LTTT). A secondary aim was to tentatively assess efficacy. METHODS: A custom-built device comprising infrared (850 nm), red (660 nm), and violet (405 nm) LEDs was utilized. DUs were irradiated with 10 J/cm2 twice weekly for 3 weeks, with follow-up at weeks 4 and 8. Any safety concerns were documented. Patient opinion on time to deliver, feasibility, and pain visual analogue score (VAS; 0-100, 100 most severe) was collected. Patient and clinician DU global assessment VAS were documented. DUs were evaluated by laser Doppler perfusion imaging pre- and post-irradiation. RESULTS: In all, 14 DUs in eight patients received a total of 46 light exposures, with no safety concerns. All patients considered LTTT 'took just the right amount of time' and was 'feasible', with a low associated mean pain VAS of 1.6 (SD: 5.2). Patient and clinician global DC VAS improved during the study (mean change: -7.1 and -5.2, respectively, both p < .001). DU perfusion significantly increased post-irradiation. CONCLUSIONS: LTTT for DUs is safe, feasible, and well tolerated. There was an early tentative suggestion of treatment efficacy.

Quantifying Digital Ulcers in Systemic Sclerosis: Reliability of Computer-Assisted Planimetry in Measuring Lesion Size.

OBJECTIVE: Digital ulcers are a major problem in patients with systemic sclerosis (SSc), causing severe pain and impairment of hand function. In addition, digital ulcers heal slowly and sometimes become infected, which can lead to gangrene and necessitate amputation if appropriate intervention is not taken. A reliable, objective method for assessing digital ulcer healing or progression is needed in both the clinical and research arenas. This study was undertaken to compare 2 computer-assisted planimetry methods of measurement of digital ulcer area on photographs (ellipse and freehand regions of interest [ROIs]), and to assess the reliability of photographic calibration and the 2 methods of area measurement. METHODS: Photographs were taken of 107 digital ulcers in 36 patients with SSc spectrum disease. Three raters assessed the photographs. Custom software allowed raters to calibrate photograph dimensions and draw ellipse or freehand ROIs. The shapes and dimensions of the ROIs were saved for further analysis. RESULTS: Calibration (by a single rater performing 5 repeats per image) produced an intraclass correlation coefficient (intrarater reliability) of 0.99. The mean ± SD areas of digital ulcers assessed using ellipse and freehand ROIs were 18.7 ± 20.2 mm2 and 17.6 ± 19.3 mm2 , respectively. Intrarater and interrater reliability of the ellipse ROI were 0.97 and 0.77, respectively. For the freehand ROI, the intrarater and interrater reliability were 0.98 and 0.76, respectively. CONCLUSION: Our findings indicate that computer-assisted planimetry methods applied to SSc-related digital ulcers can be extremely reliable. Further work is needed to move toward applying these methods as outcome measures for clinical trials and in clinical settings.

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 10min, up to 90min 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.

Does the Clinical Context Improve the Reliability of Rheumatologists Grading Digital Ulcers in Systemic Sclerosis?

OBJECTIVE: Digital ulcers (DUs) are often a primary end point in systemic sclerosis (SSc; scleroderma) clinical trials, although the reliability of rheumatologists grading DUs is poor to moderate at best. DU assessment in recent trials has been based upon visual inspection alone, which potentially misses "real-world" clinical contextual information. Our aim was to investigate whether this clinical information improves the reliability of rheumatologists grading DUs. A secondary aim was to assess agreement between patients and rheumatologists. METHODS: Eighty images of a range of digital lesions were collected from patients with SSc with the clinical context: pain (severity and temporal relationship), lesion duration, and discharge (patient reported and clinician observed). Raters received all images either with or without the clinical context, and graded these images (using a custom-built interface) on an ordinal scale of severity: no ulcer, inactive ulcer, or active ulcer. Patients also graded their lesion(s) on the same scale. RESULTS: Fifty-one rheumatologists from 15 countries completed the study (26 without and 25 with context): 4,590 (including 510 repeated) image gradings were obtained. Context did not significantly increase (without and with context) either intra- (0.64, 0.71) or interrater (0.32, 0.36) reliability. Pain (visual analog scale and temporal relationship) and discharge (patient reported and clinician observed) were associated with increased lesion severity, and duration with reduced severity. Agreement between individual patients and rheumatologists was poor without and with context (0.19, 0.28). CONCLUSION: The overall intra- and interrater reliability of DU grading did not significantly improve with the clinical context. Agreement between patients and rheumatologists was poor.

Simulating nailfold capillaroscopy sequences to evaluate algorithms for blood flow estimation.

The effects of systemic sclerosis (SSc)--a disease of the connective tissue causing blood flow problems that can require amputation of the fingers--can be observed indirectly by imaging the capillaries at the nailfold, though taking quantitative measures such as blood flow to diagnose the disease and monitor its progression is not easy. Optical flow algorithms may be applied, though without ground truth (i.e. known blood flow) it is hard to evaluate their accuracy. We propose an image model that generates realistic capillaroscopy videos with known flow, and use this model to quantify the effect of flow rate, cell density and contrast (among others) on estimated flow. This resource will help researchers to design systems that are robust under real-world conditions.