Dynamic blood flow imaging with 99mTc-hydroxymethylene diphosphonate as a therapeutic response marker in patients with Raynaud's phenomenon.

We evaluated the predictive value of dynamic blood flow scintigraphy with 99mTc-HDP (hydroxymethylene diphosphonate) for therapeutic response in patients with Raynaud's phenomenon (RP). Eighty patients who underwent dynamic blood flow scintigraphy using the one-hand chilling method were enrolled. We analyzed the quantitative variables as the ratio of chilled fingers to ambient fingers (CAfinger), that of the chilled hand to ambient hand (CAhand), and that of chilled fingers to ambient palm (FPR) (CAFPR) at 15 and 30 s after 99mTc-HDP bolus injection. Total cumulative radioactivity counts for 180 s were obtained. We evaluated the clinical utility of these quantitative parameters with other clinical variables, including RP severity, therapeutic compliance, types of RP, and scintigraphic interpretation of findings in patients with RP. Fifty-two patients showed poor therapeutic response. There were significant differences between good- and poor-therapeutic responder groups in RP intensity (p = 0.003), CAfinger15s (p = 0.008), CAfinger30s (p = 0.002), CAfinger180s (p = 0.011), CAhand15s (p = 0.008), CAhand30s (p = 0.007), CAhand180s (p = 0.017), CAFPR30s (p = 0.004), and CAFPR180s (p = 0.002). After multivariate logistic regression analysis, only CAfinger30s (p = 0.002) had an independent predictive value of the therapeutic response. 99mTc-HDP dynamic blood flow scintigraphy could be helpful in predicting the therapeutic response in patients with RP.

Raynaud phenomenon and microvasculopathy in systemic sclerosis: multi-modality imaging for diagnosis and evaluation.

PURPOSE OF REVIEW: To describe the clinical significance of and the diagnostic approach to Raynaud phenomenon (RP) in the peripheral extremities and the heart. RECENT FINDINGS: Nailfold capillaroscopy has recently been standardized in an expert consensus paper. Abnormal capillaroscopy in combination with specific autoantibody profiles and clinical signs are highly predictive of progression of RP to systemic sclerosis (SSc). Magnetic resonance imaging (MRI) can also perform tissue characterization of both the extremities and the heart. Microvascular wall abnormalities detected using nailfold capillaroscopy in patients with SSc may lead to deposition of erythrocyte-derived iron, due to microhemorrhages, which may predispose to fibrosis. MRI can assess the presence of iron using T2∗ measurements. SUMMARY: RP is a hallmark of the microvasculopathy in SSc and can affect both the peripheral extremities and the heart. Nailfold capillaroscopy is the current gold standard for the evaluation of the peripheral microvasculature. Other imaging modalities include thermography, laser Doppler-derived methods, 99m Tc-pertechnetate hand perfusion scintigraphy, power Doppler ultrasonography, dynamic optical coherence tomography, MRI, and photoacoustic imaging, but these are currently not widely used. Cardiac RP can be investigated with positron emission tomography or cardiovascular magnetic resonance, with the latter offering the additional possibility of tissue characterization and iron content quantification secondary to microhemorrhages.

Nailfold capillaroscopy.

Nailfold capillaroscopy is a safe and well-established method for the assessment of structural alterations of the microcirculation. It is a crucial tool in the investigation and monitoring of patients presenting with Raynaud's phenomenon. Detection of the characteristic "scleroderma pattern" on capillaroscopy may indicate an underlying rheumatic disease, particularly systemic sclerosis (SSc). Herein, we highlight the practical aspects of videocapillaroscopy, including image acquisition and analysis, with mention of dermoscopy. Special emphasis is placed on standardized use of terminology to describe capillary characteristics. Systematic evaluation of images in discerning the normal from the abnormal using the validated European Alliance of Associations for Rheumatology (EULAR) Study Group consensus reporting framework is paramount. In addition to the relevance of capillaroscopy in the (very) early diagnosis of SSc, its emerging predictive value (especially capillary loss) for new organ involvement and disease progression is underscored. We further provide capillaroscopic findings in selected other rheumatic diseases.

External clinical validation of automated software to identify structural abnormalities and microhaemorrhages in nailfold videocapillaroscopy images.

OBJECTIVES: Automated systems to analyse nailfold videocapillaroscopy (NVC) images are needed to promptly and comprehensively characterise patients with systemic sclerosis (SSc) or Raynaud's phenomenon (RP). We previously developed, and validated in-house, a deep convolutional neural network-based algorithm to classify NVC-captured images according to the presence/absence of structural abnormalities and/or microhaemorrhages. We present its external clinical validation. METHODS: A total of 1,164 NVC images of RP patients were annotated by 5 trained capillaroscopists according to the following categories: normal capillary; dilation; giant capillary; abnormal shape; tortuosity; microhaemorrhage. The images were also presented to the algorithm. Matches and discrepancies between algorithm predictions and those annotations obtained by consensus of ≥3 or ≥4 interobservers were analysed. RESULTS: Consensus among ≥3 capillaroscopists was achieved in 86.9% of images, 75.8% of which were correctly predicted by the algorithm. Consensus among ≥4 experts occurred in 52.0% of cases, in which 87.1% of the algorithm's results matched with those of the expert panel. The algorithm's positive predictive value was >80% for microhaemorrhages and unaltered, giant or abnormal capillaries. Sensitivity was >75% for dilations and tortuosities. Negative predictive value and specificity were >89% for all categories. CONCLUSIONS: This external clinical validation suggests that this algorithm is useful to assist in the diagnosis and follow-up of SSc or RP patients in a timely manner. It may also be helpful in the management of patients with any pathology presenting with microvascular changes, as the algorithm has been designed to also be useful for research aiming at extending the usage of nailfold capillaroscopy to more conditions.

Hyperspectral imaging in systemic sclerosis-associated Raynaud phenomenon.

BACKGROUND/PURPOSE: Lack of robust, feasible, and quantitative outcomes impedes Raynaud phenomenon (RP) clinical trials in systemic sclerosis (SSc) patients. Hyperspectral imaging (HSI) non-invasively measures oxygenated and deoxygenated hemoglobin (oxyHb and deoxyHb) concentrations and oxygen saturation (O2 sat) in the skin and depicts data as oxygenation heatmaps. This study explored the potential role of HSI in quantifying SSc-RP disease severity and activity. METHODS: Patients with SSc-RP (n = 13) and healthy control participants (HC; n = 12) were prospectively recruited in the clinic setting. Using a hand-held camera, bilateral hand HSI (HyperMed™, Waltham, MA) was performed in a temperature-controlled room (22 °C). OxyHb, deoxyHb, and O2 sat values were calculated for 78-mm2 regions of interest for the ventral fingertips and palm (for normalization). Subjects underwent a cold provocation challenge (gloved hand submersion in 15 °C water bath for 1 min), and repeated HSI was performed at 0, 10, and 20 min. Patients completed two patient-reported outcome (PRO) instruments: the Raynaud Condition Score (RCS) and the Cochin Hand Function Scale (CHFS) for symptom burden assessment. Statistical analyses were performed using the Mann-Whitney U test and a mixed effects model (Stata, College Station, TX). RESULTS: Ninety-two percent of participants were women in their 40s. For SSc-RP patients, 69% had limited cutaneous SSc, the mean ± SD SSc duration was 11 ± 5 years, and 38% had prior digital ulcers-none currently. Baseline deoxyHb was higher, and O2 sat was lower, in SSc patients versus HC (p < 0.05). SSc patients had a greater decline in oxyHb and O2 sat from baseline to time 0 (after cold challenge) with distinct rewarming oxyHb, O2 sat, and deoxyHb trajectories versus HCs (p < 0.01). There were no significant correlations between oxyHb, deoxyHb, and O2 sat level changes following cold challenge and RCS or CHFS scores. CONCLUSION: Hyperspectral imaging is a feasible approach for SSc-RP quantification in the clinic setting. The RCS and CHFS values did not correlate with HSI parameters. Our data suggest that HSI technology for the assessment of SSc-RP at baseline and in response to cold provocation is a potential quantitative measure for SSc-RP severity and activity, though longitudinal studies that assess sensitivity to change are needed.

Does the use of nail cosmetics interfere with the reporting of nailfold capillaroscopy?

Capillaroscopy is a non-invasive tool evaluating the nail-fold capillaries, especially in approach to Raynaud's phenomenon (RP) and scleroderma (SSc) spectrum of diseases. It was recommended that the patients should not use any cosmetic procedure involving the nailfold to avoid misinterpretations. Therefore, we aimed to find the problems of using or recent removal of the nail polishes/artificial nails/henna before doing capillaroscopy. During 10 years, we looked for all capillaroscopy reports and nail fold images of patients who referred for capillaroscopy and had used or recently removed nail polish/artificial nail/henna in order to find the presence of any artifacts or misinterpretations in reports. Sixty-three patients were identified that had used or removed the nail cosmetic during 10 days before capillaroscopy. In patients who used nail polish, removed their nail polish, used artificial nails, or removed the artificial nails, and those using henna, 16.2%, 36.4%, 3.8%, 0%, and 1.4% of nail folds showed some stains in the upper part of the nail fold area, respectively, that had no interference with the report due to their distinct color. However, few areas were covered with polish stains in patients who removed the polish recently. The presence of nail cosmetics including nail polishes, henna, and artificial nails at the time of capillaroscopy does not induce a significant misinterpretation in capillaroscopy. However, some colored stains which were mostly distinguishable from hemorrhages could be seen. The removal of them 10 days before the time of capillaroscopy did not decrease the cosmetic artifacts. Key Points • The presence of nail cosmetics including nail polishes, henna, and artificial nails at the time of capillaroscopy does not induce a significant misinterpretation in capillaroscopy. • The removal of nail polish 10 days before the time of capillaroscopy did not decrease the procedure artifacts. • The removal of nail polish 10 days before capillaroscopy increased the area of artifacts and coverage of the study background.

Repeatability of high-resolution laser Doppler images of the hands in patients with systemic sclerosis and secondary Raynaud's phenomenon.

OBJECTIVES: The objective of the study was to establish the repeatability of baseline diagnostic images of the dorsum of the hands acquired using a high-resolution laser Doppler imager in patients with Raynaud's phenomenon secondary to systemic sclerosis (SSc). METHODS: The dorsal side of the hands of 22 patients (8 male 14 female), age range 29-73, median 62, with SSc and secondary Raynaud's phenomenon were imaged over two consecutive days at approximately the same time using a Moor Instruments' high-resolution laser Doppler imaging unit. The images were analysed by taking regions of interest at discrete locations in the images to calculate dimensionless values of flux (PU). Repeatability of the diagnostic investigation was assessed using methods described by Bland and Altman and by also plotting the results from visit 1 against visit 2 and calculating the line of best fit. RESULTS AND CONCLUSIONS: Based on the criteria that 95% of all measurement differences should be within a factor of 1.96 of the standard deviations of the mean values, then high-resolution laser Doppler imaging technique is probably repeatable when acquiring and analysing baseline images of patients with Raynaud's phenomenon secondary to SSc. However, a larger study with more patients is required to prove this conclusively-as only data from 19 patients were analysed (3 patients were not included due to technical issues)-and was therefore susceptible to marked clinical variations in patients presenting on different days for the investigations.

Assessing scleroderma patterns with superb microvascular imaging: is it possible? New prospects for ultrasound.

Nailfold videocapillaroscopy is the gold standard for the early differentiation of primary and secondary Raynaud's phenomenon. Advances in high-frequency ultrasound with superb microvascular imaging show significant potential for exploring structural changes that were previously inaccessible. Ultrasound makes it possible to assess not only the superficial layers of the skin but also structural microvascular abnormalities in the deep layers of the nail fold. There is potential for identifying a 'scleroderma pattern', which presents with the loss of continuous vascular arches above and below the nail plate in transverse and longitudinal scans of the nail folds. The 'active' pattern presents with the loss of the junctions between vascular signals, which is not seen in the 'early' pattern. Severely reduced vascularity with avascular areas in both of the nail fold zones is seen in a 'late' pattern. The quality of the evaluation is highly dependent on how experienced the sonographer is. This is the first detailed description of every pattern assessed through superb microvascular imaging, including high-quality images for a better understanding of the technique.

Role of short courses on nailfold capillaroscopy in obtaining abilities for the identification of microvasculopathy in patients with Raynaud's phenomenon.

INTRODUCTION: An early distinction between "normal" and "abnormal" capillaroscopic pattern during the first visit to a dermatologist has a crucial significance for a diagnostic management of Raynaud's phenomenon (RP). There exists a question about the level of expertise sufficient to evaluate the microcirculation. AIM: To evaluate the utility of short courses on NFC among dermatologists and medical students in obtaining sufficient abilities for the identification of microvasculopathy in patients with RP using videocapillaroscope and handheld dermoscope. METHODS: Both groups participated in 1-h course on NFC. Before the course, participants were asked to classify 20 videocapillaroscopic and 10 dermoscopic capillaroscopic pictures into "normal" or "abnormal" pattern. Each picture was displayed on a separate slide MS PowerPoint for 10 s. The evaluation was repeated soon after the course. RESULTS: A total of 36 dermatologists and 49 medical students were enrolled. The rate of properly classified dermoscopic and videodermoscopic pictures increased after the course in both groups, but students improved the accuracy of classification on dermoscopic pictures to the greater extent than dermatologists. The rate of correctly recognized pictures with "abnormal" pattern was significantly greater than ones with "normal" pattern at the baseline and after the course, independently of imagining tool. CONCLUSIONS: Short courses on NFC may improve the classification of capillaroscopic images, even in medical staff with no previous experience in NFC. The recognition of capillaroscopic abnormalities seems to be easier than obtaining the confidence that evaluated picture has "normal pattern."

Nailfold capillaroscopy in the rheumatological current clinical practice in Italy: results of a national survey.

This cross-sectional online study was designed by the study group on Capillaroscopy and Microcirculation in Rheumatic Diseases (CAP) of the Italian Society of Rheumatology (SIR) to provide an overview of the management of nailfold capillaroscopy in Italian rheumatology centers. Therefore, SIR distributed the survey to its members in July 2021, and each center's physician with the most expertise in capillaroscopy completed the questionnaire. The survey was completed by 102 centers, with at least one representative from each Italian region. Ninety-three centers perform capillaroscopy, and 52 (56) conduct more than 200 investigations annually. Seventy-eight (84%) of respondents have more than five years of experience with the technique, and 75 centers (80.6%) have received certification from specific national or international training courses. In 85 centers, a videocapillaroscope with 200x magnification is employed (91.4%). The average waiting period for the examination is 2.4 months, and less than 3 months in 64 of the locations (68.8%). The study demonstrates that capillaroscopy is an integral part of both the diagnostic phase of Raynaud's phenomenon and the monitoring of autoimmune connective tissue diseases (CTDs). However, the reporting methods and timing of patient followup are heterogeneous.

Nailfold capillaroscopy: tips and challenges.

Although nailfold capillaroscopy (NFC) appears to have a bright future in clinical practice, the lack of familiarity with the technique and how to interpret its outcomes is major barriers which have made nailfold capillaroscopy an underutilized method in standard clinical practice. Traditional methods for assessment and measurement of capillary patterns, density, and blood flow are falling behind and face some challenges. In fact, there have been calls for improvement, hence the recent publication of the standardization of NFC by the EULAR Study Group on Microcirculation in Rheumatic Diseases. Nailfold capillaroscopy has the advantage of being a non-invasive technique that provides a window into the digital microcirculation. This paved the way for a rapidly growing interest in using capillaroscopy parameters as outcome measures in research. In standard clinical practice, whilst its main application is in the identification of an underlying systemic sclerosis spectrum disorder in patients presenting with Raynaud's phenomenon, its use has expanded to include other clinical features possibly suggestive of an underlying connective tissue disease. This article presents the challenges, provides tips, and highlights the exciting potential of nailfold capillaroscopy in standard practice.

The shadow zone of capillaroscopy in the classification of the Raynaud's phenomenon.

Raynaud's phenomenon (RP) is a frequent clinical finding in the general population that can be observed across multiple medical specialties and nailfold videocapillaroscopy is a first line imaging tool to early differenziate primitive and secondary forms of RP. According to the criteria of LeRoy and Medsger normal nailfold capillaries characterize a primary RP. The recognition of vascular alterations at capillaroscopy is the key to a correct framing of the phenomenon. Capillaroscopy is of significant practical value as it allows a reliable predictive assessment of the developmental risk of the disorder. However, to date, the variety of nomenclature for subjects affected by RP generates uncertainty in patient management and in the possibility of comparing studies. The capillaroscopic findings have a very broad range of normality and a significant presence of non specific microvascular abnormalities are reported also in patients with primary RP. The presence of these non specific vascular changes can make it difficult to differenziate primary and secondary RP. Here we highlight some critical points in the capillaroscopic distinction of primary and secondary RP and relaunch the debate on the classification of the RP because it is likely that what we identify today as the primary RP (pRP) collects different clinical entities with different prognostic significance and different therapeutic needs.

Magnetic resonance characterisation of primary Raynaud's phenomenon.

The objective findings of phalangeal T2-weighted hyperintense and T1-weighted hypointense bone marrow signal on MRI without features of seronegative arthropathy or osteomyelitis may assist clinicians in making a diagnosis in the appropriate clinical context.

Hallazgos capilaroscópicos y características clínicas en pacientes con fenómeno de Raynaud primario y secundario / Capillaroscopic findings and clinical characteristics in patients with primary and secondary Raynaud's phenomenon

Objetivos: describir hallazgos de videocapilaroscopía (VCP) en pacientes con fenómeno de Raynaud primario (FRP) y secundario (FRS); comparar características demográficas y clínicas entre ambos. Materiales y métodos: estudio observacional, analítico, transversal. Se documentaron edad, ocupación, tiempo de evolución del FR, enfermedad del tejido conectivo (ETC) y características capilaroscópicas. Las VCP se informaron como patrón normal, inespecífico o SD temprano, activo y tardío. Se realizó estadística descriptiva. Para variables categóricas se empleó Chi² o test exacto de Fisher; para variables continuas, t test o Man Whitney, considerando estadísticamente significativa p<0,05. Resultados: se realizaron 290 VCP. En pacientes con FRP (n:122), 18% (n:23) fue normal y 81% (n:99) con patrón inespecífico. En pacientes con FRS (n:168), 8% fue normal, 42% con patrón inespecífico y 51% con patrón SD (25% temprano, 44% activo, 31% tardío). Se hallaron diferencias estadísticamente significativas: tiempo de evolución de FR en meses (12 vs 36, p<0,01), VCP normal (18,85% vs 7,4%, p<0,01), patrón inespecífico (81,14% vs 41%, p<0,01) en pacientes con FRP vs. FRS. Conclusiones: en pacientes con FRS predominó el patrón SD, mientras que en aquellos con FRP fue superior el patrón normal e inespecífico. El FRS se asoció a mayor tiempo de evolución.

Objectives: to describe videocapillaroscopy (VCP) findings in patients with primary Raynaud's phenomenon (PRP) and secondary (SRP); compare demographic and clinical characteristics between both. Materials and methods: observational, analytical, cross-sectional study. Age, occupation, evolution time of RP, connective tissue disease (CTD) and capillaroscopic characteristics were documented. The VCP were reported as normal, nonspecific or early, active, and late SD pattern. Descriptive statistics were performed. Chi² or Fisher's exact test were used for categorical variables; for continuous variables t test or Man Whitney, considering statistically significant p<0.05. Results: 290 VCP were performed. In patients with PRP (n:122), 18% (n:23) were normal and 81% (n:99) non-specific. In patients with SRP (n:168), 8% were normal, 42% non-specific and 51% with SD pattern (25% early, 44% active, 31% late). We found statistically significant differences: time of evolution of RP in months (12 vs. 36, p<0.01), normal VCP (18.85% vs 7.4%, p<0.01), non-specific pattern (81.14% vs 41%, p<0.01) in patients with PRP vs SRP. Conclusions: in patients with FRS predominated the SD pattern, while in those with FRP the normal and nonspecific pattern was superior. FRS was associated with a longer evolution time.

Nailfold capillaroscopy in systemic diseases: short overview for internal medicine.

Nailfold capillaroscopy (NFC) is now one of the main imaging tools in systemic sclerosis and imposed over time as an easy, non-invasive method for the nailfold microvascular bed assessment. In qualitative NFC normal pattern is characterized by homogeneous, parallel fashion arrangement of the last capillaries row as well as by capillaries with hairpin or non-specific variations like tortuous and/ or crossing shape. Nailfold capillaroscopy is strongly recommended for evaluation of all patients with Raynaud phenomenon. Appearance of giant capillaries is chronologically the first relevant finding for scleroderma spectrum disorders development (systemic sclerosis, dermatomyositis, undifferentiated and mixed connective tissue disease). Collapses of the giant loops generate microhemorrhages and further capillary loss with subsequent hypoxia, and neoangiogenesis seen as ramified/ bushy capillaries. Nailfold capillaroscopy is indicated especially in systemic sclerosis, being also included in the classification criteria. Based on these major NFC pathologic findings (giant capillaries, microhemorrhages, avascularity and neoangiogenesis), three evolutive stages were described in systemic sclerosis, namely the early, active, and late scleroderma pattern. In other connective tissue diseases than those scleroderma-related, like systemic lupus erythematosus, psoriatic arthritis, or antiphospholipid syndrome, the interest for capillaroscopy is growing, but the attempts of defining specific characteristics failed until now. Besides qualitative NFC, semiquantitative and quantitative capillaroscopic assessments were proposed for more accurate evaluation. Lately, automated systems are under development. There is still need of more studies to sustain the nailfold capillaroscopy validity as diagnostic and prognostic test.

Photoacoustic and high-frequency ultrasound imaging of systemic sclerosis patients.

INTRODUCTION: Systemic sclerosis starts with an early phase characterized by Raynaud's phenomenon, puffy fingers/hands, autoantibodies, and a scleroderma nailfold microscopic pattern. Alterations in the nailfold microscopic pattern are not evident in all early SSc patients. Photoacoustics (PA) and high-frequency ultrasound (HFUS) could fulfill this need. The former can measure oxygen saturation while the latter can measure skin thickening. We hypothesize that photoacoustics and high-frequency ultrasound can distinguish (early) SSc patients from individuals with primary Raynaud's phenomenon (PRP) by measuring oxygenation of the fingertip and skin thickening. METHODS: We compared measurements of oxygenation and skin thickness of the third finger between (early) SSc patients and PRP individuals and healthy controls. The spearman rank correlation was used to analyze an association between capillary density and oxygen saturation of the fingers. RESULTS: Thirty-one adult subjects participated in this study: twelve patients with SSc, 5 patients with early SSc, 5 volunteers with PR, and 9 healthy controls. We found a significant difference in oxygen saturation between (early) SSc patients (80.8% ± 8.1 and 77.9% ± 10.5) and individuals with PRP (93.9% ± 1.1). Measurements of skin thickening showed a significant difference in (early) SSc patients compared to individuals with PRP (0.48 ± 0.06 mm and 0.51 ± 0.16 mm vs. 0.27 ± 0.01 mm). There was no significant difference between healthy and PRP individuals in oxygenation or skin thickening. CONCLUSION: Photoacoustic and high-frequency ultrasound could help to distinguish between (early) SSc, PRP, and healthy individuals in both oxygenation and skin thickening.

Raynaud Phenomenon in Systemic Sclerosis: Does Digital Thermal Monitoring Correlate to Specific Nailfold Videocapillaroscopy Abnormalities?

OBJECTIVE: Early diagnosis of systemic sclerosis (SSc) is imperative, and Raynaud phenomenon (RP) is an important component of progressive vasculopathy. Nailfold videocapillaroscopy (NVC) is a well-established tool that can quantify structural vascular abnormalities. Digital thermal monitoring (DTM) assesses microvascular functional dysfunction related to thermoregulation. In this study, we investigated the correlation of NVC patterns and DTM variables in patients with SSc. METHODS: Patients with SSc according to the 2013 American College of Rheumatology/European League Against Rheumatism criteria who consented and enrolled in the clinical care registry had NVC and DTM performed. For NVC, the number of capillaries (density), measurement of apical diameter (dimension), presence or absence of hemorrhages, and number of abnormal shapes were assessed to categorize 3 different qualitative patterns: early, active, and late. For DTM, Doppler ultrasound hyperemic, low frequency, blood velocity of radial artery, and fingertip vascular function were assessed, and a vascular reactivity index (VRI) measurement was automated. Statistical evaluation was performed by nonparametric tests to assess the correlation of NVC and VRI. RESULTS: Thirty-one SSc subjects with interpretable NVC and DTM performed on the same day were included in the study. VRI was progressively higher in SSc patients with early, active, and late NVC patterns of microangiopathy (P < 0.0001). There was a significant negative correlation between VRI and microhemorrhages scores (r = -0.363, P = 0.044). CONCLUSION: Our study suggests that more advanced vasculopathy correlates to reduced microvascular function as detected by DTM and more advanced structural abnormalities detected by NVC. NVC and DTM may provide different aspects of vasculopathy quantification and complement each other as investigative tools.

Performance of laser-derived imaging for assessing digital perfusion in clinical trials of systemic sclerosis-related digital vasculopathy: A systematic literature review.

BACKGROUND: Raynaud's phenomenon (RP) and digital ulcers (DU) are important features of digital vasculopathy in systemic sclerosis (SSc). Laser Doppler flowmetry (LDF), Laser Doppler Imaging (LDI) and Laser Speckle Contrast Imaging (LSCI) can non-invasively quantify digital perfusion and may be useful outcome measures for SSc-RP and/or SSc-DU clinical trials. We undertook a systematic literature review to evaluate the performance of laser-derived imaging as outcome measures in clinical trials of SSc-related digital vasculopathy. METHODS: Standardized searches (EMBASE and MEDLINE) identified trials that incorporated laser-derived imaging of digital vasculopathy in adult subjects with SSc. Data was extracted (by >2 reviewers) on study design, laser endpoints, and reported outcomes. Study quality was assessed using validated instruments (PROSPERO 2019:CRD42019142409). RESULTS: Of 126 identified articles, full data extraction was undertaken from 29 studies. Fifteen randomized and 14 non-randomized trials (total of 689 SSc patients with mean 23.8/study) have evaluated a broad range of oral, intravenous and topical interventions for SSc-RP (n = 11), digital perfusion alone (n = 15) and SSc-DU (n = 3). The studies were published between 1987 and 2019 (17/29 since 2010) and incorporated LDF (11/29), LDI (15/29) and LSCI (4/29, including one with LDF); with LSCI and LDI more commonly incorporated in recent trials. Most studies (16/29, 55%) reported improvement in digital perfusion following intervention, often concordant with patient- and clinician-derived outcomes. CONCLUSIONS: Establishing laser-derived methods as a surrogate for SSc-related digital vasculopathy will greatly support drug development. Full-field perfusion of the digits (with/without provocation testing) is a promising clinical trial outcome measure for trials of SSc-related digital vasculopathy.