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.

Low body weight and involuntary weight loss are associated with Raynaud's phenomenon in both men and women.

Objectives: Low body weight is an easily assessable cause of Raynaud's phenomenon (RP), and is frequently overlooked by clinicians. We aim to investigate the association of low body weight (body mass index < 18.5 kg/m2), involuntary weight loss, and nutritional restrictions with the presence of RP.Method: Participants from the Lifelines Cohort completed a validated self-administered connective tissue disease questionnaire. Subjects who reported cold-sensitive fingers and biphasic or triphasic colour changes were considered to suffer from RP. Patient characteristics, anthropometric measurements, and nutritional habits were collected. Statistical analyses was stratified for gender.Results: Altogether, 93 935 participants completed the questionnaire. The prevalence of RP was 4.2% [95% confidence interval (CI) 4.1-4.4%], and was three-fold higher in women than in men (5.7% vs 2.1%, p < 0.001). Subjects with RP had a significantly lower daily caloric intake than those without RP. Multivariate analysis, correcting for creatinine level, daily caloric intake, and other known aetiological factors associated with RP, revealed that low body weight [men: odds ratio (OR) 5.55 (95% CI 2.82-10.93); women: 3.14 (2.40-4.10)] and involuntary weight loss [men: OR 1.32 (1.17-1.48); women: 1.31 (1.20-1.44)] were significantly associated with the presence of RP. Low-fat diet was also associated with RP in women [OR 1.27 (1.15-1.44)].Conclusion: Low body weight and prior involuntary weight loss are associated with an increased risk of RP in both men and women. This study emphasizes that low body weight and weight loss are easily overlooked risk factors for RP, and should be assessed and monitored in subjects with 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.

Impact and associates of digital pitting in patients with systemic sclerosis: a pilot study.

Objective: Despite being a cardinal clinical sign of systemic sclerosis (SSc), digital pitting has been little studied. Our objective was to test, in a pilot study, the hypothesis that pitting is painful and associated with digital vascular disease severity.Method: Fifty patients with SSc were recruited: 25 with and 25 without digital pitting. Fingertip pain was assessed on a 0-10 scale. Thermography of both hands assessed surface temperature, allowing calculation of the distal-dorsal difference (temperature gradient) for each finger. Nailfold capillaroscopy was performed in each finger using a dermatoscope, and graded on a 0-3 scale (0 = normal; 3 = grossly abnormal).Results: In the 25 patients with digital pitting, 65 fingers in total were affected (mainly the index and middle fingers). Pain scores were higher in 'pitting' patients [median 4 (interquartile range 3-8) vs 0 (0-2), p < 0.001], and pitting patients reported that pitting impacted on activities of everyday living. Temperature gradients along the fingers did not differ significantly between patients with and without pitting (p = 0.248). Pitting patients were more likely to have 'grossly abnormal' capillaries than those without pitting, and less likely to have 'no/mild' nailfold capillary changes.Conclusions: Digital pitting is painful and impacts on hand function. Capillaroscopy findings provide further support for an association between pitting and severity of digital vascular change. Larger, more comprehensive studies are required to examine the pathophysiology of pitting and to pave the way to therapeutic intervention, ideally including preventive strategies.

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.

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.

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.

Stability of Bisexual Behavior and Extent of Viral Bridging Behavior Among Men Who Have Sex with Men and Women.

Bisexual men experience significant health disparities likely related to biphobia. Biphobia presents via several preconceptions, including that bisexuality is transitory, and that bisexual men act as viral bridges between men who have sex with men and heterosexual populations. We analyzed data from a prospective cohort of gay and bisexual men, the Multicenter AIDS Cohort Study, to test these preconceptions. Men reporting both male and female sexual partners (MSMW) between 2002 and 2009 (n = 111) were classified as behaviorally bisexual. We assessed five hypotheses over two domains (transience of bisexual behavior and viral bridging). No evidence was found supporting the transitory nature of bisexuality. Trajectories of bisexual behavior were not transient over time. We found little evidence to support substantial viral bridging behavior. Notably, HIV-positive MSMW reported lower proportions of female partners than HIV-negative MSMW. Our results provide no empirical support for bisexual transience and scant support for viral bridging hypotheses. Our results provide key data showing that male bisexual behavior may be stable over long time periods and that behaviorally bisexual men's risk to female sexual partners may be lower than expected.

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.

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.

Sexual-Orientation Differences in Positive Youth Development: The Mediational Role of Bullying Victimization.

OBJECTIVES: To examine sexual-orientation differences in positive youth development, and how bullying victimization mediated these differences in a sample of adolescents. METHODS: In 2007 to 2008, positive youth development was measured in 1870 adolescents from US schools and after-school programs in 45 states by using the validated Five Cs model of competence, confidence, connection, character, and caring/compassion. Sexual-minority youths (6.8%) reported having same- or both-gender sexual attractions. Nonattracted youths (4.2%) reported having no sexual attractions. RESULTS: Compared with sexual-minority youths, heterosexual and nonattracted youths had lower odds of being a victim of bullying. Heterosexual and nonattracted youths also had higher average scores in competence, confidence, and connection, but these associations between sexual orientation and positive youth development scores were partly attributable to lack of bullying victimization. CONCLUSIONS: Designing, implementing, and evaluating interventions that reduce bullying can give sexual-minority youths access to several building blocks of health and well-being.

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.

History of surgical debridement, anticentromere antibody, and disease duration are associated with calcinosis in patients with systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc)-related calcinosis is often painful and disabling. Our aim was to examine its clinical and serological associates, and whether it is possible to build a model to predict the presence of calcinosis. METHOD: This was a retrospective cross-sectional study. Clinical and demographic variables examined were: age, gender, disease subtype, SSc duration, previous intravenous prostanoid infusions, surgical debridement and/or amputation, autoantibody status (anticentromere and antitopoisomerase), pulmonary fibrosis, and pulmonary hypertension. Univariable logistic regression was used to investigate associations between demographic and clinical factors and the odds of clinical calcinosis, then multivariable regression to obtain adjusted odds ratios (ORs) and confidence intervals (CIs). RESULTS: A total of 317 patients (86% female, median age 60 years) were included: 94 (30%) had clinically apparent calcinosis. Age and gender were similar in those with and without calcinosis. Only surgical debridement (OR 3.55, 95% CI 1.71-7.53), anticentromere status (OR 2.32, 95% CI 1.27-4.32), and disease duration (OR 1.08, 95% CI 1.04-1.11) remained significant predictors after adjusting for other variables. In combination, the selected variables explained approximately 18% of the variation in the outcome but did not grant sufficient predictive power to discriminate between those with and without calcinosis [Nagelkerke's R(2) = 0.18, area under the receiver operating characteristic curve (AuROC) = 0.51, both adjusted for optimism]. CONCLUSIONS: History of surgical debridement, positive anticentromere antibody, and disease duration were independently associated with calcinosis. However, the low explanatory and discriminatory power of a multiple logistic regression model suggests there are other important predictors of calcinosis unaccounted for in this analysis.

Running Backwards: Consequences of Current HIV Incidence Rates for the Next Generation of Black MSM in the United States.

Black men who have sex with men (MSM) in the United States are disproportionately impacted by HIV. To better understand this public health problem, we reviewed the literature to calculate an estimate of HIV incidence among Black MSM. We used this rate to model HIV prevalence over time within a simulated cohort, which we subsequently compared to prevalence from community-based samples. We searched all databases accessible through PubMed, and Conference on Retroviruses and Opportunistic Infections abstracts for HIV incidence estimates among Black MSM. Summary HIV incidence rates and 95 % confidence intervals (CIs) were calculated using random effects models. Using the average incidence rate, we modeled HIV prevalence within a simulated cohort of Black MSM (who were all HIV-negative at the start) from ages 18 through 40. Based on five incidence rates totaling 2898 Black MSM, the weighted mean incidence was 4.16 % per year (95 % CI 2.76-5.56). Using this annual incidence rate, our model predicted that 39.94 % of Black MSM within the simulated cohort would be HIV-positive by age 30, and 60.73 % by 40. Projections were similar to HIV prevalence found in community-based samples of Black MSM. High HIV prevalence will persist across the life-course among Black MSM, unless effective prevention and treatment efforts are increased to substantially reduce HIV transmission among this underserved and marginalized population.