A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's.

OBJECTIVE: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP. METHODS: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites. RESULTS: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated. CONCLUSION: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.

A Phase II randomized controlled trial of oral prednisolone in early diffuse cutaneous systemic sclerosis (PRedSS).

OBJECTIVES: Although the painful and disabling features of early diffuse cutaneous SSc (dcSSc) have an inflammatory basis and could respond to corticosteroids, corticosteroids are a risk factor for scleroderma renal crisis. Whether or not they should be prescribed is therefore highly contentious. Our aim was to examine safety and efficacy of moderate-dose prednisolone in early dcSSc. METHODS: PRedSS set out as a Phase II, multicentre, double-blind randomized controlled trial, converted to open-label during the Covid-19 pandemic. Patients were randomized to receive either prednisolone (∼0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. Co-primary endpoints were the HAQ Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures reflecting pain, itch, fatigue, anxiety and depression, and helplessness. Target recruitment was 72 patients. RESULTS: Thirty-five patients were randomized (17 prednisolone, 18 placebo/control). The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was -0.10 (97.5% CI: -0.29, 0.10), P = 0.254, and in mRSS -3.90 (97.5% CI: -8.83, 1.03), P = 0.070, both favouring prednisolone but not significantly. Patients in the prednisolone group experienced significantly less pain (P = 0.027), anxiety (P = 0.018) and helplessness (P = 0.040) than control patients at 3 months. There were no renal crises, but sample size was small. CONCLUSION: PRedSS was terminated early primarily due to the Covid-19 pandemic, and so was underpowered. Therefore, interpretation must be cautious and results considered inconclusive, indicating the need for a further randomized trial. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03708718.

Nailfold capillaroscopy-how many fingers should be examined to detect abnormality?

Objectives: Nailfold capillaroscopy is being increasingly used by rheumatologists in the diagnosis of SSc. However, assessment of all nailfolds can be time-consuming in a busy outpatient clinic. Our aim was to answer the question as to how many (and which) fingers a clinician should routinely assess to capture accurately the true state. Methods: A total of 2994 assessments (by an international panel of expert observers) of 1600 images from 173 participants (101 with SSc, 22 with primary RP and 50 healthy controls) were included in this analysis. Seven single-finger or finger combinations (derived from the middle and ring fingers) were then tested for sensitivity for the presence of two markers of capillary abnormality [presence of giant capillaries and an SSc grade (early, active or late)] compared with assessment of all eight fingers. Results: For the eight-finger gold standard, sensitivity against the diagnostic criteria was 74.6% (53.0% for the presence of giants alone and 73.1% for image grade alone). Examining only one finger gave low sensitivity (ranging from right middle 31.7% to left ring 46.6%). Examining both ring fingers gave a sensitivity of 59.8%, whereas examining the four-finger combination of both ring and both middle fingers gave a sensitivity of 66.7%. Conclusion: During routine capillaroscopic examination, ideally all eight nailbeds (excluding thumbs) should be examined, otherwise some abnormalities will be missed. Examining only four fingers reduces capillaroscopy sensitivity.

Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate).

OBJECTIVES: Assess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study. METHODS: Patients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96. RESULTS: Overall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was -3.1 (6.3 (-5.4 to -0.9)) for placebo and -5.6 (9.1 (-8.9 to-2.4)) for tocilizumab at week 48 and -9.4 (5.6 (-8.9 to -2.4)) for placebo-tocilizumab and -9.1 (8.7 (-12.5 to -5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period. CONCLUSIONS: Skin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab. TRIAL REGISTRATION NUMBER: NCT01532869; Results.

Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study.

OBJECTIVES: Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). METHODS: The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). RESULTS: 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. CONCLUSIONS: Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. TRIAL REGISTRATION NUMBER: NCT02339441.

Patient acceptable symptom state in scleroderma: results from the tocilizumab compared with placebo trial in active diffuse cutaneous systemic sclerosis.

Objectives: Patient acceptable symptom state (PASS) as an absolute state of well-being has shown promise as an outcome measure in many rheumatologic conditions. We aimed to assess whether PASS may be effective in active diffuse cutaneous SSc differentiating active from placebo. Methods: Data from the phase 2 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (faSScinate) trial were used, which compared tocilizumab (TCZ) vs placebo over 48 weeks followed by an open-label TCZ period to 96 weeks. Three different types of PASS questions were evaluated at weeks 8, 24, 48 and 96, including if a current state would be acceptable over time as a yes vs no response and Likert scales about how acceptable a current state is if remaining over time. Additional outcomes assessed included modified Rodnan skin score, HAQ disability index (HAQ-DI), physician and patient global assessments on a visual analogue scale, CRP and ESR. Results: The placebo group consisted of 44 patients and the TCZ group had 43 patients. At baseline, 33% achieved a PASS for all three PASS questions, with the proportion increasing to 69, 71 and 78%, respectively, at 96 weeks. Changes in PASS scores showed a moderately negative correlation with HAQ-DI and patient and physician global assessments visual analogue scales, which indicates expected improvements as PASS improved. The PASS question, 'Considering all of the ways your scleroderma has affected you, how acceptable would you rate your level of symptoms?' showed significant correlations with patient-reported outcomes and differentiating placebo vs TCZ at 48 weeks (P = 0.023). Conclusion: PASS may be used as a patient-centred outcome in SSc, especially as a 7-point Likert scale. Further validation is required to determine the utility as an outcome measure in trials and clinical practice.

Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study.

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features. Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined. Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = -0.53, P < 0.0001). Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.

Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial.

BACKGROUND: Systemic sclerosis is a rare disabling autoimmune disease with few treatment options. The efficacy and safety of tocilizumab, an interleukin 6 receptor-α inhibitor, was assessed in the faSScinate phase 2 trial in patients with systemic sclerosis. METHODS: We did this double-blind, placebo-controlled study at 35 hospitals in Canada, France, Germany, the UK, and the USA. We enrolled adults with progressive systemic sclerosis of 5 or fewer years' duration from first non-Raynaud's sign or symptom. Patients were randomly assigned (1:1) to weekly subcutaneous tocilizumab 162 mg or placebo. The primary endpoint was the difference in mean change from baseline in modified Rodnan skin score at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT01532869. FINDINGS: We enrolled 87 patients: 43 assigned to tocilizumab and 44 assigned to placebo. The least squares mean change in modified Rodnan skin score at 24 weeks was -3·92 in the tocilizumab group and -1·22 in the placebo group (difference -2·70, 95% CI -5·85 to 0·45; p=0·0915). The least squares mean change at 48 weeks was -6·33 in the tocilizumab group and -2·77 in the placebo group (treatment difference -3·55, 95% CI -7·23 to 0·12; p=0·0579). In one of several exploratory analyses, fewer patients in the tocilizumab group than in the placebo group had a decline in percent predicted forced vital capacity at 48 weeks (p=0·0373). However, we detected no significant difference in disability, fatigue, itching, or patient or clinician global disease severity. 42 (98%) of 43 patients in the tocilizumab group versus 40 (91%) of 44 in the placebo group had adverse events. 14 (33%) versus 15 (34%) had serious adverse events. Serious infections were more common in the tocilizumab group (seven [16%] of 43 patients) than in the placebo group (two [5%] of 44). One patient died in relation to tocilizumab treatment. INTERPRETATION: Tocilizumab was not associated with a significant reduction in skin thickening. However, the difference was greater in the tocilizumab group than in the placebo group and we found some evidence of less decline in forced vital capacity. The efficacy and safety of tocilizumab should be investigated in a phase 3 trial before definitive conclusions can be made about its risks and benefits. FUNDING: F Hoffmann-La Roche, Genentech.

Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS).

OBJECTIVES: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. METHODS: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. RESULTS: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. CONCLUSIONS: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. TRIAL REGISTRATION NUMBER: NCT02339441.

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.

Intra-and inter-observer reliability of nailfold videocapillaroscopy - A possible outcome measure for systemic sclerosis-related microangiopathy.

OBJECTIVES: Our aim was to assess the reliability of nailfold capillary assessment in terms of image evaluability, image severity grade ('normal', 'early', 'active', 'late'), capillary density, capillary (apex) width, and presence of giant capillaries, and also to gain further insight into differences in these parameters between patients with systemic sclerosis (SSc), patients with primary Raynaud's phenomenon (PRP) and healthy control subjects. METHODS: Videocapillaroscopy images (magnification 300×) were acquired from all 10 digits from 173 participants: 101 patients with SSc, 22 with PRP and 50 healthy controls. Ten capillaroscopy experts from 7 European centres evaluated the images. Custom image mark-up software allowed extraction of the following outcome measures: overall grade ('normal', 'early', 'active', 'late', 'non-specific', or 'ungradeable'), capillary density (vessels/mm), mean vessel apical width, and presence of giant capillaries. RESULTS: Observers analysed a median of 129 images each. Evaluability (i.e. the availability of measures) varied across outcome measures (e.g. 73.0% for density and 46.2% for overall grade in patients with SSc). Intra-observer reliability for evaluability was consistently higher than inter- (e.g. for density, intra-class correlation coefficient [ICC] was 0.71 within and 0.14 between observers). Conditional on evaluability, both intra- and inter-observer reliability were high for grade (ICC 0.93 and 0.78 respectively), density (0.91 and 0.64) and width (0.91 and 0.85). CONCLUSIONS: Evaluability is one of the major challenges in assessing nailfold capillaries. However, when images are evaluable, the high intra- and inter-reliabilities suggest that overall image grade, capillary density and apex width have potential as outcome measures in longitudinal studies.

Quantitative outcome measures for systemic sclerosis-related Microangiopathy - Reliability of image acquisition in Nailfold Capillaroscopy.

BACKGROUND: Nailfold capillaroscopic parameters hold increasing promise as outcome measures for clinical trials in systemic sclerosis (SSc). Their inclusion as outcomes would often naturally require capillaroscopy images to be captured at several time points during any one study. Our objective was to assess repeatability of image acquisition (which has been little studied), as well as of measurement. METHOD: 41 patients (26 with SSc, 15 with primary Raynaud's phenomenon) and 10 healthy controls returned for repeat high-magnification (300×) videocapillaroscopy mosaic imaging of 10 digits one week after initial imaging (as part of a larger study of reliability). Images were assessed in a random order by an expert blinded observer and 4 outcome measures extracted: (1) overall image grade and then (where possible) distal vessel locations were marked, allowing (2) vessel density (across the whole nailfold) to be calculated (3) apex width measurement and (4) giant vessel count. Intra-rater, intra-visit and intra-rater inter-visit (baseline vs. 1week) reliability were examined in 475 and 392 images respectively. A linear, mixed-effects model was used to estimate variance components, from which intra-class correlation coefficients (ICCs) were determined. RESULTS: Intra-visit and inter-visit reliability estimates (ICCs) were (respectively): overall image grade, 0.97 and 0.90; vessel density, 0.92 and 0.65; mean vessel width, 0.91 and 0.79; presence of giant capillary, 0.68 and 0.56. These estimates were conditional on each parameter being measurable. CONCLUSION: Within-operator image analysis and acquisition are reproducible. Quantitative nailfold capillaroscopy, at least with a single observer, provides reliable outcome measures for clinical studies including randomised controlled trials.

Correlates of Alcohol Use Among Patrons of Alcohol Consumption Venues in Botswana.

This study evaluated the correlates of three alcohol measures using a cross-sectional survey conducted among patrons of alcohol-serving venues in Gaborone, Botswana from October 2012 to February 2013. Using logistic regression, we found that engaging in higher levels of sexual risk behaviors was significantly associated with frequent drinking (at least 3 times a week), heavy episodic drinking (more than 6 standard units of alcohol at least weekly) and probable alcohol dependence (AUDIT score ≥20). Additionally, having higher levels of alcohol expectancies that increase the risk of HIV infection was significantly associated with probable alcohol dependence. Although HIV knowledge was generally high in this population, there is need for HIV prevention and alcohol harm reduction efforts to address the role of alcohol in increasing HIV risk and encourage the adoption of safer drinking patterns and the modification of alcohol expectancies.

Calcium channel blockers for primary Raynaud's phenomenon.

BACKGROUND: Calcium channel blockers are the most commonly prescribed drugs for people with primary Raynaud's phenomenon. Primary Raynaud's phenomenon is a common condition characterised by an exaggerated vasospastic response to cold or emotion: classically the digits (fingers and toes) turn white, then blue, then red. This is an update of the review first published in 2014. OBJECTIVES: To assess the effects of different calcium channel blockers for primary Raynaud's phenomenon as determined by attack rates, severity scores, participant-preference scores and physiological measurements. SEARCH METHODS: For this update the Cochrane Vascular Trial Search Co-ordinator searched the Specialised Register (last searched January 2016) and the Cochrane Register of Studies (CENTRAL) (2015, Issue 12). In addition the TSC searched clinical trials databases. SELECTION CRITERIA: Randomised controlled trials evaluating the effects of oral calcium channel blockers for the treatment of primary Raynaud's phenomenon. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the trials for inclusion and their quality, and extracted the data. Data extraction included adverse events. We contacted trial authors for missing data. MAIN RESULTS: We included seven randomised trials with 296 participants. Four trials examined nifedipine and the remainder nicardipine. Comparisons were with placebo in six trials and with both dazoxiben and placebo in one trial (only the nifedipine versus placebo data were used within this review). Treatment with oral calcium channel blockers was minimally effective in primary Raynaud's phenomenon at decreasing the frequency of attacks (standardised mean difference of 0.23; 95% confidence interval (CI) 0.08 to 0.38, P = 0.003). This translates to 1.72 (95% CI 0.60 to 2.84) fewer attacks per week on calcium channel blockers compared to placebo. One trial provided details on duration of attacks reporting no statistically significant difference between the nicardipine and placebo groups (no P value reported). Only two trials provided any detail of statistical comparisons of (unvalidated) severity scores between treatment groups: one of these trials (60 participants) reported a mean severity score of 1.55 on placebo and 1.36 on nicardipine, difference 0.2 (95% CI of difference 0 to 0.4, no P value reported) and the other trial (three participants only with primary Raynaud's phenomenon) reported a median severity score of 2 on both nicardipine and placebo treatment (P > 0.999) suggesting little effect on severity. Participant-preference scores were included in four trials, but in only two were results specific to participants with primary Raynaud's phenomenon, and scoring systems differed between trials: scores differed between treatments in only one trial, in which 33% of participants on placebo and 73% on nifedipine reported improvement in symptoms (P < 0.001). Physiological measurements were included as outcome measures in five trials (different methodologies were used in each): none of these trials found any statistically significant between-treatment group differences. Treatment with calcium channel blockers appeared to be associated with a number of adverse reactions, including headaches, flushing and oedema (swelling). Overall, the trials were classed as being at low or unclear risk of bias; and the quality of the evidence presented was moderate for number of attacks, very low for duration of attacks, high for severity scores and low for patient preference scores. AUTHORS' CONCLUSIONS: The randomised controlled trials included in this review provide moderate quality evidence that oral calcium channel blockers are minimally effective in the treatment of primary Raynaud's phenomenon as measured by the frequency of attacks and high-quality evidence that they have little effect on severity. We are unable to comment on duration of attacks or on patient preference due to the very low and low quality of evidence as a result of small sample sizes in the included studies and the variable data quality of outcome measures.

Alcohol Consumption and Risky Sexual Behavior Among Persons Attending Alcohol Consumption Venues in Gaborone, Botswana.

Alcohol use is a known key risk factor associated with risky sexual behavior that contributes to HIV transmission. This cross-sectional study used time location sampling to investigate alcohol use and risky sexual behaviors that occurred after ingesting alcohol among 609 patrons of alcohol venues in Gaborone, Botswana. Alcohol Use Disorders Identification Test (AUDIT) scores were categorized as low (1-7), medium (8-15), and high (16+) for analysis. Logistic regression models stratified by gender assessed the association between alcohol use and condom use at last sex after drinking alcohol. Among females, the odds of condom use during last sex after drinking alcohol were significantly lower for high compared to low AUDIT scores (AOR = 0.17, 95% CI 0.06-0.54). Among males, factors significantly associated with condom use at last sex after alcohol use were low levels of education (primary level compared to university and above AOR = 0.13; 95% CI 0.03-0.55) and beliefs that alcohol use did not increase risky sexual behaviors (AOR = 0.26; 95% CI 0.11-0.62). HIV prevention interventions should target females and emphasize sexual risks associated with alcohol use.

Consensus best practice pathway of the UK Scleroderma Study Group: digital vasculopathy in systemic sclerosis.

OBJECTIVE: Digital vasculopathy (comprising RP, digital ulceration and critical digital ischaemia) is responsible for much of the pain and disability experienced by patients with SSc. However, there is a limited evidence base to guide clinicians in the management of SSc-related digital vasculopathy. Our aim was to produce recommendations that would be helpful for clinicians, especially for those managing patients outside specialist centres. METHODS: The UK Scleroderma Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including digital vasculopathy. RESULTS: This overview presents the background and best practice consensus pathways for SSc-related RP, digital ulceration and critical ischaemia. Examples of drug therapies, including doses, are suggested in order to inform prescribing practice. CONCLUSION: A number of treatment algorithms are provided that are intended to provide the clinician with accessible reference tools for use in daily management.

Calcium channel blockers for primary Raynaud's phenomenon.

BACKGROUND: Calcium channel blockers are the most commonly prescribed drugs for people with primary Raynaud's phenomenon. Primary Raynaud's phenomenon is a common condition characterised by an exaggerated vasospastic response to cold or emotion: classically the digits (fingers and toes) turn white, then blue, then red. OBJECTIVES: To assess the effects of different calcium channel blockers for primary Raynaud's phenomenon as determined by attack rates, severity scores, participant-preference scores and physiological measurements. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched February 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 1). In addition the TSC searched clinical trials databases. SELECTION CRITERIA: Randomised controlled trials evaluating the effects of oral calcium channel blockers for the treatment of primary Raynaud's phenomenon. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the trials for inclusion and their quality, and extracted the data. Data extraction included adverse events. We contacted trial authors for missing data. MAIN RESULTS: We included seven randomised trials with 296 participants. Although overall all the trials were classed as being at low or unclear risk of bias, the sample size of the included trials was small and there was unclear reporting of outcomes. Four trials examined nifedipine and the remainder nicardipine. Comparisons were with placebo in six trials and with both dazoxiben and placebo in one trial (only the nifedipine versus placebo data were used within this review). Treatment with oral calcium channel blockers was minimally effective in primary Raynaud's phenomenon at decreasing the frequency of attacks (standardised mean difference of 0.23; 95% confidence interval (CI) 0.08 to 0.38, P = 0.003). This translates to 1.72 (95% CI 0.60 to 2.84) fewer attacks per week on calcium channel blockers compared to placebo. One trial provided details on duration of attacks reporting no statistically significant difference between the nicardipine and placebo groups (no P value reported). Only two trials provided any detail of statistical comparisons of (unvalidated) severity scores between treatment groups: one of these trials (60 participants) reported a mean severity score of 1.55 on placebo and 1.36 on nicardipine, difference 0.2 (95% CI of difference 0 to 0.4, no P value reported) and the other trial (three participants only with primary Raynaud's phenomenon) reported a median severity score of 2 on both nicardipine and placebo treatment (P > 0.999). Participant-preference scores were included in four trials, but in only two were results specific to participants with primary Raynaud's phenomenon, and scoring systems differed between trials: scores differed between treatments in only one trial, in which 33% of participants on placebo and 73% on nifedipine reported improvement in symptoms (P < 0.001). Physiological measurements were included as outcome measures in five trials (different methodologies were used in each): in none of these trials were any statistically significant between-treatment group differences found. Treatment with calcium channel blockers appeared to be associated with a number of adverse reactions, including headaches, flushing and oedema (swelling). AUTHORS' CONCLUSIONS: The randomised controlled trials included in this review provide moderate-quality evidence that oral calcium channel blockers are minimally effective in the treatment of primary Raynaud's phenomenon as measured by the frequency of attacks. However, the results of this review were limited by small sample sizes in the included studies and by variable data quality, particularly with regard to outcome measures.

Neutrophil-derived reactive oxygen species in SSc.

OBJECTIVE: Reactive oxygen species (ROS) are implicated in the pathogenesis of SSc. Neutrophils constitute a major source of ROS during inflammation. Here, we examined endogenous and stimulated ex vivo ROS production of SSc neutrophils compared with control neutrophils with and without prior priming with TNF-α. METHODS: ROS generation was measured using luminol-enhanced chemiluminescence. Neutrophils isolated from SSc patients and healthy controls were unprimed or were primed with TNF-α. ROS production was stimulated in vitro with phorbol 12-myristate 13-acetate (PMA) and formyl-met-leu-phe (fMLP). To examine the effects of serum mediators on ROS generation, control neutrophils were also stimulated with SSc or control serum. RESULTS: Neutrophil stimulation with PMA and fMLP resulted in a greater increase in ROS generation in SSc neutrophils compared with controls. However, unstimulated SSc neutrophils generated lower levels of ROS than controls. SSc neutrophils demonstrated an increased response to fMLP in the absence of in vitro TNF-α priming indicating priming of SSc neutrophils in vivo. SSc serum did not stimulate neutrophil ROS generation in vitro. CONCLUSION: SSc neutrophils are primed for ROS generation. Neutrophils binding to activated endothelium in SSc, may induce local production of ROS, perpetuating endothelial dysfunction and mediating fibrosis.

Endothelial activation and apoptosis mediated by neutrophil-dependent interleukin 6 trans-signalling: a novel target for systemic sclerosis?

OBJECTIVES: Systemic sclerosis (SSc) is a connective tissue disease associated with significant morbidity and mortality and generally inadequate treatment. Endothelial cell activation and apoptosis are thought to be pivotal in the pathogenesis of this disease, but the mechanisms that mediate this remain unknown. METHODS: Human dermal microvascular endothelial cells were cultured with healthy control neutrophils in the presence of 25% healthy control or SSc serum for 24 h. Apoptosis was measured by annexin V-FITC binding and endothelial cell activation was measured using an allophycocyanin-conjugated E-selectin antibody. Fluorescence was quantified and localised using confocal microscopy. RESULTS: SSc serum resulted in significantly increased apoptosis (p=0.006) and E-selectin expression (p=0.00004) in endothelial cells compared with control serum, effects that were critically dependent on the presence of neutrophils. Recombinant interleukin 6 (IL-6) reproduced these findings. Immunodepletion of IL-6 and the use of an IL-6 neutralising antibody decreased the effect of SSc serum on E-selectin expression. Soluble gp130, which specifically blocks IL-6 trans-signalling, negated the effect of SSc serum on both E-selectin expression and apoptosis. CONCLUSIONS: SSc serum induces endothelial cell activation and apoptosis in endothelial cell-neutrophil co-cultures, mediated largely by IL-6 and dependent on the presence of neutrophils. Together with other pathologically relevant effects of IL-6, these data justify further exploration of IL-6 as a therapeutic target in SSc.