John D. Pauling

Comparison of infrared thermography and laser speckle contrast imaging for the dynamic assessment of digital microvascular function

OBJECTIVES Laser speckle contrast imaging (LSCI) is a novel non-invasive microvascular imaging modality. The present study evaluates the validity and reliability of LSCI by comparison with infrared thermography (IRT) for the dynamic assessment of digital microvascular function in healthy volunteers. METHODS Subjects attended on 3 occasions. Simultaneous assessment of cutaneous perfusion at 3 distinct regions of interest (ROI) within the hands was undertaken using LSCI and infrared thermography (IRT) at baseline, and at 13s intervals over 15 min following a standardised local cold challenge. Endpoints for evaluation included absolute measurements at baseline and following cold stress, in addition to the characteristics of the re-warming curves (maximum % recovery and maximum gradient). Visits 1 and 2 were undertaken in identical conditions (ambient temperature 23°C) to assess reproducibility, whereas visit 3 was undertaken at a lower ambient room temperature of 18°C to evaluate responsiveness to reduction in ambient room temperature. RESULTS Fourteen healthy participants completed the study. There was greater variability in the data generated using LSCI compared with the highly damped IRT, reflecting greater sensitivity of LSCI to physiological variation and movement artefact. LSCI and IRT correlated well at baseline and following cold challenge for all endpoints (r(s) for pooled data between 0.5 and 0.65, p<0.00005). Reproducibility of both IRT and LSCI was excellent (ICCs>0.75) for absolute assessments but lower for re-warming curve characteristics. LSCI provides greater spatial resolution than IRT identifying variation in cutaneous perfusion within the hands most likely associated with the presence of arteriovenous anastamoses. Both techniques were responsive to reduction in ambient room temperature. Effect sizes were greatest for IRT than LSCI (e.g. -1.17 vs. -0.85 at ROI 1 at baseline) although this may represent heat transfer rather than altered vascular perfusion. DISCUSSION In the dynamic assessment of digital vascular perfusion, LSCI correlates well with IRT, is reproducible and responsive to reduction in ambient room temperature. Absolute measurements appear preferable to parameters derived from re-warming curve characteristics when assessing digital perfusion following cold challenge. The greater temporal and spatial resolution of LSCI compared with IRT may facilitate the development of novel assessment tools of autonomic function and digital cutaneous perfusion.

Use of laser speckle contrast imaging to assess digital microvascular function in primary Raynaud phenomenon and systemic sclerosis: a comparison using the Raynaud condition score diary

Objective. Evaluate objective assessment of digital microvascular function using laser speckle contrast imaging (LSCI) in a cross-sectional study of patients with primary Raynaud phenomenon (RP) and systemic sclerosis (SSc), comparing LSCI with both infrared thermography (IRT) and subjective assessment using the Raynaud Condition Score (RCS) diary. Methods. Patients with SSc (n = 25) and primary RP (n = 18) underwent simultaneous assessment of digital perfusion using LSCI and IRT with a cold challenge on 2 occasions, 2 weeks apart. The RCS diary was completed between assessments. The relationship between objective and subjective assessments of RP was evaluated. Reproducibility of LSCI/IRT was assessed, along with differences between primary RP and SSc, and the effect of sex. Results. There was moderate-to-good correlation between LSCI and IRT (Spearman rho 0.58–0.84, p < 0.01), but poor correlation between objective assessments and the RCS diary (p > 0.05 for all analyses). Reproducibility of IRT and LSCI was moderate at baseline (ICC 0.51–0.63) and immediately following cold challenge (ICC 0.56–0.86), but lower during reperfusion (ICC 0.3–0.7). Neither subjective nor objective assessments differentiated between primary RP and SSc. Men reported lower median daily frequency of RP attacks (0.82 vs 1.93, p = 0.03). Perfusion using LSCI/IRT was higher in men for the majority of assessments. Conclusion. Objective and subjective methods provide differing information on microvascular function in RP. There is good convergent validity of LSCI with IRT and acceptable reproducibility of both modalities. Neither subjective nor objective assessments could differentiate between primary RP and SSc. Influence of sex on subjective and objective assessment of RP warrants further evaluation.

Pulmonary artery hypertension as the presenting feature of systemic sclerosis sine scleroderma

A. KAUL, D. T. O’REILLY, R. K. SLACK, D. COLLINS, J. WALMSLEY, O. DUKE, P. D. W. KIELY St George’s Healthcare NHS Trust, London, West Suffolk Hospital, Bury St Edmonds, Great Western Hospital, Swindon and Epsom and St Helier NHS Trust, Epsom, UK Accepted 4 June 2008 Correspondence to: A. Kaul, Department of Rheumatology, Royal Free Hospital, Pond Street, London NW3 2QG, UK. E-mail: arvind.kaul@royalfree.nhs.uk

Microparticle subpopulations are potential markers of disease progression and vascular dysfunction across a spectrum of connective tissue disease

Objective Microparticles (MPs) are membrane-bound vesicles derived from vascular and intravascular cells such as endothelial cells (EMPs) and platelets (PMPs). We investigated EMP and PMP numbers across a spectrum of autoimmune rheumatic diseases (AIRDs) with the aim of comparing the levels of, and relationship between, EMPs and PMPs. Methods Patients with Systemic Lupus Erythematosus (SLE) (n = 24), Systemic Sclerosis (SSc) (n = 24), Primary Raynauds Phenomenon (RP) (n = 17) and “other CTD” (n = 15) (Primary Sjogrens Syndrome, UCTD or MCTD) as well as 15 healthy controls were recruited. EMPs and PMPs were quantified using flow cytometry. Associations between MP levels and objective functional vascular assessments were evaluated. Results SLE patients had significantly higher EMPs compared with healthy controls and SSc patients. Higher PMP levels were noted in SSc and primary RP when compared to healthy controls and ‘other CTD’ patients. A modest correlation was noted between EMP and PMP levels in healthy controls (Spearman r = 0.6, p = 0.017). This relationship appeared stronger in SLE (r = 0.72, p < 0.0001) and other CTD patients (r = 0.75, p < 0.0001). The association between EMPs and PMPs was notably less strong in SSc (r = 0.45, p = 0.014) and RP (r = 0.37, p = 0.15). A significantly lower EMP/PMP ratio was detected in SSc/RP patients in comparison to both healthy controls and SLE/other CTD patients. Higher EMP and PMP levels were associated with higher digital perfusion following cold challenge in SSc. In contrast, higher PMP (but not EMP) levels were associated with lower digital perfusion at both baseline and following cold challenge in primary RP. Higher PMP levels were associated with greater endothelial-independent dilation in patients with SLE. Conclusion MP populations differ across the spectrum of AIRDS, possibly reflecting differences in vascular cell injury and activation. MP levels are associated with functional assessments of vascular function and might have a role as novel vascular biomarkers in AIRDs. Significance and innovations Levels of circulating endothelial and platelet microparticles differ between SSc/primary RP compared with SLE and other CTDs (UCTD, MCTD and Primary Sjogrens). MP release may occur within different vascular sites across these disease groups (macrovascular and microvascular). The association between circulating MP levels and objective assessment of macro- and microvascular dysfunction within these disease areas suggests that MPs might have a useful role as novel circulating biomarkers of vascular disease within the CTDs.

Sublingual Abnormalities in Systemic Sclerosis

BackgroundSublingual frenulum abnormalities have been observed in systemic sclerosis (SSc), but the clinical significance of such features is not known. The goal of this project was to devise a reliable bedside tool to confirm the presence of sublingual frenulum abnormalities in SSc and explore potential associations with patient demographics and gastrointestinal clinical phenotype. MethodsA working group was created to develop a semiquantitative assessment tool for assessing sublingual abnormalities, the Sublingual Abnormalities Index (SAI). Sublingual frenulum thickness, frenulum length, sublingual buccal mucosa pallor, and the presence of oral telangiectasia were each individually scored using 0- to 2-point Likert scales and a composite score of the 4 domains created by summation of the individual scores. Assessment of the sublingual region of 21 patients with SSc and 8 control subjects was undertaken. An image of the sublingual frenulum was obtained using prespecified camera settings to allow assessment of interrater reliability with 2 independent blinded assessors. ResultsScores for each of the SAI domains differed between control subject and SSc population (P = 0.0003). Patients with SSc had a composite SAI score of 4.3 (SD, 0.37). None of the control subjects had a composite SAI score of more than 2. There was excellent interrater reliability between clinician assessment and each blinded assessor (Cohen &kgr;’s of 0.72 and 0.82, respectively). ConclusionsThis feasibility study confirms the presence of clinical sublingual abnormalities in SSc, which can be categorized using a simple scoring chart with moderate to near-perfect interrater agreement. The functional significance and pathogenesis of this abnormality warrant further study.

Consensus best practice pathway of the UK Systemic Sclerosis Study group:management of cardiac disease in systemic sclerosis

Objective Cardiac disease in SSc can manifest in various ways and is associated with a poor prognosis. There is little evidence on how best to detect and manage cardiac disease in SSc. Our objective was to produce an expert consensus best practice pathway for the management of cardiac disease in SSc. Methods The UK Systemic Sclerosis Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including cardiac disease. A multidisciplinary task force was convened. The guidelines were partly informed by a comprehensive literature review. Results A best practice pathway for cardiac disease (with a focus on primary cardiac disease) in SSc is presented, including approaches for early detection and standard pharmacological and device therapies. Due to the benefits, shared care and a multidisciplinary approach are recommended. A future research agenda has been formulated in response to the relative lack of understanding of the natural history of primary cardiac disease that was highlighted by the initiative. Conclusion The physician should be alert to the possibility of cardiac disease in SSc; it is best managed within a multidisciplinary team including both rheumatologists and cardiologists. This pathway provides a reference for all physicians managing patients with SSc.

Factors associated with sustained remission in rheumatoid arthritis in patients treated with anti-tumour necrosis factor (anti-TNF)

Anti–tumor necrosis factor (anti‐TNF) antibody has revolutionized the treatment of rheumatoid arthritis (RA), and remission is now a realistic possibility for patients. Despite widespread use of anti‐TNFs, predicting which patients are most likely to attain a sustained good response to these treatments remains challenging. Our objective was to undertake a systematic review of the literature to evaluate existing evidence for demographic and clinical factors associated with the achievement of sustained remission in individuals with RA treated with anti‐TNF therapy.

Abnormal cardiac enzymes in systemic sclerosis: a report of four patients and review of the literature

Cardiac involvement in systemic sclerosis (SSc) is heterogeneous and can include primary involvement of the myocardium, pericardium and coronary arteries or be secondary to cardiac complications of pulmonary and renal disease. Primary cardiac involvement in SSc is uncommon but can result in ventricular dysfunction, organ failure, arrhythmias and death. It can remain clinically silent and the prevalence is likely to be under-reported. We report four cases of SSc associated with a raised serum troponin T (TnT), in a proportion of whom cardiac MRI myocardial abnormalities were detected. These cases highlight the heterogeneity of cardiac involvement in SSc, the role of cardiac MRI and promising biochemical responses to immunosuppression. Cardiac biomarkers such as TnT may be useful screening tools to identify subclinical cardiac disease and assess response to therapeutic intervention.

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.

Vasodilation is not the only approach to the management of cutaneous ulceration in systemic sclerosis

Digital ulceration (DU) is a major cause of pain, decreased work capacity and increased reliance on other in systemic sclerosis (SSc) [1]. Phosphodiesterase inhibitors and endothelin receptor antagonist therapy have an important role in SSc-DU management [2]. A 49-year-old lady with a 9-year history of diffuse cutaneous SSc presented with recurrent painful DU despite treatment with diltiazem, ramipril and candesartan. The addition of sildenafil, and subsequently bosentan, did not accelerate DU healing or prevent the emergence of new painful DUs (Fig. 1A). The identification of significant calcinosis cutis (Fig. 1B) led to commencement of minocycline (100 mg bd) which achieved rapid (within 4 months), complete and sustained healing of all active ulceration with no further new cutaneous ulceration (Fig. 1C). Treatment was complicated by minocycline-induced hyperpigmentation (Fig. 1D), but the patient did not wish to discontinue treatment. The case highlights the need to consider aetiological drivers of SSc-DU when considering management. Vasodilator therapy forms the mainstay of treatment of ischaemic SSc-DU, but evidence-based strategies for the prevention and management of SSc-DU in which mechanical factors and/or calcinosis cutis contribute to aetiopathogenesis are lacking. Minocycline is a treatment option for calcinosis-related SSc-DU that is often overlooked in recommendations on SSc-DU management.