Attacks Of Raynaud's Phenomenon Research Articles

Systematic literature review to inform the Portuguese recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 non-pharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment.

Placebo response in Raynaud's Phenomenon clinical trials: The prominent role of regression towards the mean: Placebo response in Raynaud's Phenomenon

BackgroundSubstantial placebo response has been observed in trials assessing treatments in Raynaud's Phenomenon (RP), which makes any treatment effect difficult to detect. However, whether this response is due to a real placebo effect or to other nonspecific effects, such as regression towards the mean (RTM), has not been explored. Our objectives were to explore and quantify placebo response in RP, and to evaluate the magnitude of RTM contribution. MethodsWe combined trial-level and individual-level data from a series of n-of-1 trials and a network meta-analysis, respectively. Main outcomes were the daily frequency and the mean duration of RP attacks, as well as the Raynaud's Condition Score (RCS). We estimated the placebo response by the mean difference between the placebo period (or arm) and the baseline. RTM was estimated by the relationship between placebo response and baseline, and with Galton squeeze plots. Finally, we simulated the effect of the threshold used for inclusion in clinical trials on RTM. FindingsWe observed a large and significant placebo response from both individual and trial data for RCS [-1.20 (-1.63, -0.77) and -0.65 (-0.89, -0.41)] and the daily frequency of RP [-0.61 (-0.85, -0.37) and -0.75 (-0.95, -0.54)]. Outcome at baseline was significantly associated with placebo response, suggesting the presence of RTM. The latter was confirmed on individual data, through Galton squeeze plots. InterpretationPlacebo response is large in RP trials, and likely due to regression towards the mean rather than ‘true’ placebo effect. This should be carefully considered when designing future trials. FundingThis work has been partially supported by MIAI @ Grenoble Alpes (ANR-19-P3IA-0003).

Treatment of resistant Raynaud's phenomenon with single-port thoracoscopic sympathicotomy: One-year follow-up

ObjectiveFollow-up of patients with treatment-resistant Raynaud's phenomenon (RP) one-year after single-port thoracoscopic sympathicotomy (SPTS). MethodsEight patients (six males, two females, median age of 45 years) with treatment-resistant RP underwent left-sided SPTS at the third rib (R3), unilaterally. Questionnaires were taken, and number and duration of RP attacks were reported over a 2-week period. Perfusion was assessed with a cooling and recovery procedure at baseline and one year after SPTS. Furthermore, laser speckle contrast analysis, pulse wave velocity, heart rate variability and nailfold capillary microscopy were performed. ResultsOne year after SPTS the duration of the attacks of was reduced with 1.9 h in the left hand versus 0.3 h in the right hand. Furthermore, three aspects of the questionnaire showed a significant improvement (role limitations due to physical health (p = 0.017), pain (p = 0.027) and physical functioning (p = 0.025)). The total area under the curve of the total cooling and recovery procedure of the left hand was larger one year after surgery (101 (75–140) at baseline versus 118 (95–190) one year post-operatively, p = 0.012), implying a better perfusion in the fingers. This was mainly due to the improvement during the recovery phase (21 (1–41) at baseline versus 38 (24–43) one year post-operatively, p = 0.028). ConclusionOne year after unilateral R3 SPTS the benefit with regard to the majority of outcome variables persisted, though some effects seem to attenuate. Long-term effects and long-term follow-up results will be investigated in an on-going study. Clinical trial registration numberNCT02680509.

The clinical relevance of Raynaud's phenomenon symptom characteristics in systemic sclerosis.

Raynaud's phenomenon (RP) is a cardinal feature of systemic sclerosis (SSc) and manifests with pain, digital colour change, sensory symptoms, and impaired function. SSc-RP is exacerbated by cold exposure (RP 'attacks') but many patients report persistent symptoms of background digital ischaemia. The aim of our study was to examine the significance of RP with digital colour change with or without symptoms, and persistent colour change in between attacks. Patients with SSc responses were obtained from the Patient Survey of experiences of Raynaud's Phenomenon (PASRAP). We enquired about symptoms associated with Raynaud's attacks, and persistent symptoms in between attacks. Data were analysed as descriptive statistics with appropriate parametric/non-parametric testing. Relevant PASRAP survey question data from 747 evaluable SSc patients from across three continents were analysed. Isolated colour change was rare (29/484, 6%). Digital ulcers were more common in SSc-RP associated with other sensory symptoms (42.1% vs. 24.1%, P=0.057) and more readily treated with phosphodiesterase-type 5 inhibitors (22.5% vs. 10.3%%, P=0.124). Over one-third of patients (n=92/239, 38%) reported persistent colour change in between Raynaud's attacks. Patients with persistent colour change were more likely to have pulmonary arterial hypertension (15.2% vs. 7.5%, P=0.057) and be treated with calcium channel blockers (54.3% vs. 39.0%, P=0.021). SSc-RP with colour change and other symptoms and/or or persistent decolourisation in between attacks were more likely to have vascular complications of SSc and be treated with vascular therapies. Future research should explore the judicious use of vascular therapies as a potential form of disease modification in SSc. Key Points • Isolated colour change without other symptoms is rare in SSc patients. • SSc patients often identify persistent symptoms in between attacks of RP. • SSc-RP with colour change and other symptoms, or persistent decolourisation, may have greater disease severity and be treated with vascular therapies.

O15 Using a smartphone app to characterise and quantify skin colour changes in Raynaud's attacks

Abstract Background/Aims The lack of objective outcome measures for Raynaud's phenomenon (RP) has been a major limiting factor in development of effective treatments. At present, the Raynaud's Condition Score (RCS) is the only validated outcome measure, and is highly subjective. Mobile phone technology could provide a way forward. We have developed a smartphone app for RP monitoring that guides the patient through the process of capturing images of their hands during RP episodes, as well as capturing other data through post-attack and daily questionnaires. One of the objectives of our research programme (reported here) was to compare digital image (photographic) parameters to the RCS. Methods 40 patients with RP (8 with primary RP, 32 with RP secondary to systemic sclerosis) were recruited (40 female, median age (range): 57 years (25-74), median (range) duration of RP symptoms: 17 (0-53) years). Patients were given a smartphone handset with a pre-installed Raynaud’s Monitoring app and were trained on how to use it/take usable photographs. They were then asked to take photographs of RP attacks over a 14 day period and also to record the RCS for each episode. The app specifically prompts the patient to take a picture of their hand every minute during an attack, until confirmation is given that the attack is complete. At a 2nd visit, the handsets, images, and data were collected for analysis. The mean colour change during each RP attack was quantified (semi-automated method) by the Bhattacharyya distance (BD) in colour space between a region of interest (e.g. a section of a digit) and a control region (dorsal hand). BD was then compared to the RCS using ANOVA, after controlling for patient variability in the range of RCS values used by each patient. Results A total of 3,030 images were collected, describing 229 RP attacks. The median RCS reported was 6 (inter-quartile range [IQR]: 4), while the median for BD was 5.6 (IQR 3.2). ANOVA showed that measured values of the mean image BD were significantly different when different values of RCS were recorded by the patient (p < 0.001), i.e. attacks where patients selected different values of RCS had significantly different values of BD. Across all attacks/patients the F-value from ANOVA for RCS was 76.2, suggesting that the variation in BD for different values of RCS is much greater than the variation in BD for any one value of RCS. Conclusion Patients successfully used a smartphone app to collect photographs and data during episodes of RP. A strong association was found between skin colour change (via BD) and the gold-standard RCS. Mobile phone-documented colour change therefore has potential as an objective measure of RP. Further validation work is now required, as well as studies examining sensitivity to change. Disclosure G. Dinsdale: None. J. Manning: None. A. Herrick: None. M. Dickinson: None. C. Taylor: None.

Botulinum Toxin A Treatment for Primary and Secondary Raynaud's Phenomenon in Teenagers.

Raynaud's phenomenon (RP) is a clinical syndrome characterized by recurrent episodes of digital vasospasm triggered by exposure to physical and chemical agents or emotional stress. Although many pharmacologic treatments have been tested, there is still no cure or gold standard therapy. Botulinum toxin treatment has been proved to reduce pain and increase arterial blood flow in treated hands of adult patients with RP. The aim of this study is to evaluate the efficacy of botulinum toxin A on younger than 18-year-old patients with primary and secondary RP. A single-center prospective study was performed, including 8 patients aged 14 to 17 years who were clinically diagnosed with primary or secondary RP. BTX was injected into each hand without sedation or anesthetic blockade. The primary outcome was pain reduction after BTX injection. Pain intensity was evaluated at baseline and in the first follow-up. Secondary outcomes included variations in the number and severity of RP episodes after the BTX injection. All patients stated significant pain reduction and decreased cold sensitivity, except one patient who did not feel any changes. No patients reported any loss of strength on thumb-index finger. BTX injection is a simple, noninvasive, and cost-effective treatment alternative, offering an important nonsurgical therapeutic option for the pediatric population. It could also help optimize the dose of other treatments used in these patients. The most commonly observed positive effect is a reduction in the pain associated with RP attacks. Further studies are needed to confirm these results.

Comparative efficacy and safety of treatments for secondary Raynaud's phenomenon: a systematic review and network meta-analysis of randomised trials.

Several pharmacological treatments are available for secondary Raynaud's phenomenon, but there is uncertainty regarding the best options. We aimed to assess and compare the benefits and harms of treatments available for secondary Raynaud's phenomenon. We did a systematic review and network meta-analysis of randomised controlled trials (RCTs) of pharmacological treatments. We searched for systematic reviews published in MEDLINE and the Cochrane Database of Systematic Reviews up to Jan 31, 2017, and for RCTs published from inception to Sept 24, 2019 in MEDLINE, Embase, and ClinicalTrials.gov. We included double-blind RCTs (parallel or crossover) that compared two or more pharmacological treatments or placebo in patients with secondary Raynaud's phenomenon. Individual patient data were obtained for one unpublished RCT. Three researchers independently screened the texts and extracted the data. Efficacy outcomes included severity (on a ten-point scale), daily frequency, and mean duration of Raynaud's phenomenon attacks. We also examined tolerability and acceptability. Pairwise meta-analyses and Bayesian random-effects network meta-analyses were used to synthesise data. This study is registered with PROSPERO (CRD42017057518). We included 58 RCTs in the analysis, comprising 3867 patients (3540 [91·5%] with secondary Raynaud's phenomenon) and 15 classes of drugs. Phosphodiesterase 5 (PDE5) inhibitors were more effective than placebo for frequency (mean difference -0·36 [95% credibility interval -0·69 to -0·04]), severity (-0·34 [-0·66 to -0·03]), and duration (-3·42 [-6·62 to -0·29]) of attacks (low to moderate level of evidence). Calcium channel blockers (CCBs) were superior to placebo for frequency (-0·35 [-0·67 to -0·02]) and severity (-0·84 [-1·25 to -0·45]) of attacks (low level of evidence). For severity of attacks, selective serotonin-reuptake inhibitors (-1·54 [-2·68 to -0·41]; very low level of evidence) and oral prostacyclin receptor agonists (-0·48 [-0·80 to -0·16]; low level of evidence) were superior to placebo. No other drug classes were significantly superior to placebo with regard to efficacy outcomes. Compared with placebo, tolerability was lower for PDE5 inhibitors (incidence rate ratio for serious adverse events or early study exit due to adverse events 3·30 [95% CrI 1·49 to 7·55]) and CCBs (3·13 [1·33 to 7·04]). For all outcomes, global heterogeneity and between-study variance ranged from low (I2=0% and τ2=0·0 for attack severity and duration) to moderate (I2=41% and τ2=0·2 for tolerability). The overall risk of bias was judged to be low in 22 (38%), high in ten (17%), and unclear in 26 (45%) RCTs. PDE5 inhibitors and CCBs are the most effective pharmacological options, albeit with moderate efficacy and a low level of evidence. Current evidence does not support the use of any other drug in secondary Raynaud's phenomenon. None.

Evolving Symptom Characteristics of Raynaud's Phenomenon in Systemic Sclerosis and Their Association With Physician and Patient-Reported Assessments of Disease Severity.

Assessment of Raynaud's phenomenon (RP) in systemic sclerosis (SSc) is reliant on self-report. The Raynaud's Condition Score (RCS) diary assumes discrete episodic RP attacks, although not all SSc patients identify with this paradigm. We investigated the clinical associations of SSc-RP symptom characteristics and the evolution of SSc-RP symptoms with disease progression. A cross-sectional study at UK and US sites captured digital color changes of SSc-RP and patients' ability to identify with diagrammatic representations (and descriptive stems) of 4 distinct theoretical SSc-RP patterns (progressing severity A through D) reflecting progressively severe SSc-RP experiences. SSc-RP self-management and symptom evolution were explored. Patient demographics, the clinical phenotype, the Scleroderma Health Assessment Questionnaire (SHAQ), the 2-week RCS diary, and patient and physician global assessments were collected. We enrolled 107 patients with SSc (with questionnaires returned by 94). A higher number of self-reported digital color changes of SSc-RP were associated with increased SSc-RP symptom severity but not with the SSc clinical phenotype. Patients could identify with distinct patterns of SSc-RP. These patterns were associated with disease duration, global disease severity, and conceptually linked physician and patient assessments of peripheral vascular severity (e.g., SHAQ RP subscale and RCS diary parameters), but not with conceptually unrelated outcomes (e.g., SHAQ breathing subscale). SSc-RP characteristics and symptom severity evolve during the disease course. Patients identify with distinct patterns of SSc-RP that may relate to progression of the obliterative microangiopathy of SSc. Difficulty distinguishing discrete SSc-RP attacks from persistent digital ischemia in patients with advanced SSc could influence diary-based approaches to assessing SSc-RP, with implications for future clinical trials.

The effects of a single carbon dioxide and hot water hand bath on acral perfusion in systemic sclerosis: A randomized, clinical study.

Secondary Raynaud's phenomenon is the most common manifestation of systemic sclerosis, affecting more than 99% of systemic sclerosis patients, and a major cause of morbidity. Frequent and prolonged secondary Raynaud's phenomenon attacks not only cause severe discomfort and pain but also ischemic acral tissue damage. In addition to vasoactive drugs, carbon dioxide (CO2) hand bath and hot water bath are potential non-pharmacological treatment options which can be self-administered by affected patients at any time. In order to compare the efficacy of these two physical measures, this randomized, clinical study evaluated the effects of a single CO2 hand bath in patients with systemic sclerosis and secondary Raynaud's phenomenon and a healthy control group versus a single hot water hand bath on acral perfusion in systemic sclerosis by Doppler ultrasonography. None of the patients had currently digital ulcers, a vasoactive medication or a concomitant vascular disease. CO2 immersion induced an acute hemodynamic response, whereas hot water immersion had no significant effect on acral perfusion in systemic sclerosis.

Microcirculation disorders of the oral cavity in patients with primary Raynaud phenomenon.

INTRODUCTION Raynaud phenomenon is a medical condition in which the spasm of the arteries causes episodes of reduced blood flow. Potential disorders in the microcirculation of the oral mucosa may promote the occurrence of lesions. OBJECTIVES The aim of the study was to investigate the association of the frequency of oral cavity lesions with oral microcirculatory dysfunction in patients with primary Raynaud phenomenon (PRP) in comparison with healthy control group. PATIENTS AND METHODS Measurements of oral capillary flow were performed using laser doppler flowmetry (LDF) in 61 patients with PRP. In a group of 31 of 61 patients (group 1), the measurements were made during a Raynaud phenomenon (RP) attack. The RP attack was caused by stress initiated by the examination or the first visit itself. The RP attack was not deliberately caused by a cold test, vibration40w56 or any stress test. After 10 to 14 days, the measurements were repeated in all 61 patients and in the control group, and a dental examination was performed. Follow‑up visits were conducted every 3 months for a period of 12 months to monitor oral mucosa. RESULTS Differences in LDF were found between various anatomical points in both the PRP and control groups. On the first visit, the LDF flow in group 1 was significantly lower at all examined points in comparison with those in the control group. On the second visit, differences were observed in the LDF of the teeth and oral mucosa temperature in all patients with PRP in comparison with controls. Oral cavity lesions reported in the past and at follow‑up were significantly more common in patients with PRP. CONCLUSIONS Patients with PRP have dysfunction in the microcirculation of the oral mucosa and they more often have lesions in the oral cavity.

Patient-reported outcome instruments for assessing Raynaud's phenomenon in systemic sclerosis: A SCTC Vascular Working Group Report.

The episodic nature of Raynaud's phenomenon (RP) in systemic sclerosis (SSc) has led to a reliance on patient-reported outcome (PRO) instruments such as the Raynaud's Condition Score (RCS) diary. Little is known about the utilisation in routine clinical practice and health professional attitudes towards existing PRO instruments for assessing SSc-RP. Members of the Scleroderma Clinical Trials Consortium Vascular Working Group (SCTC-VWG, n=28) were invited to participate in a survey gauging attitudes towards the RCS diary and the perceived need for novel PRO instruments for assessing SSc-RP. Nineteen SCTC-VWG members (68% response rate) from academic units based in North America (n=9), Europe (n=8), South America (n=1) and Australasia (n=1) took part in the survey. There was broad consensus that RCS diary returns could be influenced by factors including seasonal variation in weather, efforts made by patients to avoid or ameliorate attacks of RP, habituation to RP symptoms, evolution of RP symptom characteristics with progressive obliterative microangiopathy, patient coping strategies, respondent burden and placebo effect. There was consensus that limitations of the RCS diary might be a barrier to drug development (79% of respondents agree/strongly agree) and that a novel PRO instrument for assessing SSc-RP should be developed with the input of both clinicians and patients (84% agree/strongly agree). Perceived potential limitations of the RCS diary have been identified along with concerns that such factors might impede drug development programs for SSc-RP. There is support within the systemic sclerosis community for the development of a novel PRO instrument for assessing SSc-RP.

A randomized, single-blinded cross-over trial of ischemic preconditioning in Raynaud's phenomenon

Introduction Ischemic preconditioning (IPC) is protective against future ischemia, with brief cycles of ischemia and reperfusion leading to the release of circulating endogenous compounds from ischemic cells. IPC may increase vasodilatory substances and improve Raynaud's phenomenon (RP). We hypothesized that IPC would be more effective than sham in RP treatment. Sample size required 18 participants to detect 5 fewer RP attacks per week. Methods This was a randomized single-blinded cross-over trial. The IPC intervention of inflating a standard blood pressure cuff on the upper arm (200 mmHg) and sham intervention (60 mmHg) were performed 3 times per week for 2 weeks, with a 2-week washout period between IPC and sham interventions. Cuff inflation was performed 4 times for 2.5 minutes, with 2.5 minutes between cuff inflation. Participants completed a daily diary on RP disease activity. Results Eighteen participants were enrolled (17 with secondary RP and 1 with primary RP); mean age 60.8 (SD 9.4) years, 89% female; and mean number of RP attacks/2 weeks in screen was 16.9 (SD 11.3). With IPC versus sham, results were not significant including an increase of 0.5 RP episodes/week (SD: 10.0; p = 0.84), decrease of 55.6 minutes per week (SD 516.4; p = 0.66), and a decrease in average severity of 0.4 points (on a scale of 0 to 10) (SD 12.9; p = 0.88). Secondary outcomes were also not significant. Conclusions No significant differences in RP disease activity were found between IPC and sham. This could be due to lack of effect of IPC on RP, too few treatments, or sham having a partial effect.

Efficacy of cilostazol for the treatment of Raynaud's phenomenon in systemic sclerosis patients.

Cilostazol is a selective inhibitor of phosphodiesterase-III with antiplatelet, antithrombotic and vasodilating properties. The aim of our study was to evaluate the effect of the drug on vasculopathy and Raynaud's phenomenon (RP), in a series of patients with systemic sclerosis (SSc), before and after cilostazol treatment. Twenty-one consecutive SSc patients with moderate or severe RP were enrolled in an open-label study. Cilostazol was administered at the dose of 100mg twice a day, for 12months. Evaluations included: daily RP attack diary documenting the frequency and duration of RP episodes, Health Assessment Questionnaire-Disability Index, scleroderma visual analogue scales (VAS), flow-mediated dilation and immunological status, including endothelin 1 and interleukin 6 plasma levels. Thirteen patients completed the study. RP duration and daily number episodes recorded over a 3-week period significantly decreased after cilostazol treatment (p=0.0049 and p=0.0067, respectively). VAS score indicated a significant amelioration of the patients' perception of RP (p=0.0117), and both baseline and post-ischemic brachial artery diameters were significantly increased after cilostazol treatment, as compared with basal values (p=0.0119 and p=0.0076, respectively). None of the patients developed digital ulcers during the study. A significant clinical improvement of RP was recorded in SSc patients undergoing cilostazol treatment. Study results indicate a potential role of cilostazol as oral maintenance therapy in SSc patients with RP.

Aminaftone in the Treatment of Raynaud’s Phenomenon in Systemic Sclerosis: New Perspectives

Objective: The aim of this study was to assess the efficacy (in terms of improved VAS Pain, Raynaud's Phenomenon attacks frequency and Raynaud’s Condition Score) of the Aminaftone in patients with Raynaud’s Phenomenon (RP) secondary to Systemic Sclerosis (SSc). Methods: Open label controlled study. We evaluated the efficacy of Aminaftone in the treatment of secondary RP in 108 patients with SSc consecutively recruited and divided in two groups. Group A: 51 Patients in treatment with Calcium Channel Blockers, prostanoids (iloprost 2ng [min/kg every 4 weeks), Endothelin Receptor Antagonist and Phosphodiesterase-5 inhibitors (Standard of Care). Group B: 57 Patients in treatment with Calcium Channel Blockers, Prostanoids, Endothelin Receptor Antagonist and Phosphodiesterase-5 inhibitors and Aminaftone (Standard of care + Aminaftone). Results: The number of RP attacks in group treated with Aminaftone (Group B) was lower than the group treated with standard therapy (Group A) from baseline to Week 48, obtaining statistically significance (Δ A -1.50 Δ B -2.10 p=0.02 95%CI). The RCS was statistically significantly different (Δ A -1.60 Δ B -2.50 p=0,04 95% CI), as was the pain VAS(Δ A -20.80 Δ B -30.60 p=0.04 95%CI) at week 48. Conclusion: The use of Aminaftone was well tolerated and improved RP as measured by RCS and pain when added to standard of care. A well-designed randomized controlled trial is needed to determine if these preliminary findings are supported

Oral N-acetylcysteine in the treatment of Raynaud's phenomenon secondary to systemic sclerosis: A randomized, double-blind, placebo-controlled clinical trial

ObjectiveTo evaluate the safety and efficacy of oral N-acetylcysteine (NAC) on digital microcirculation blood flow in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). MethodsThis was a randomized, double-blind, placebo-controlled trial in which 42 patients with SSc received oral NAC at a dose of 600mg tid (21 patients, mean age 45.6±9.5 years) or placebo (21 patients, mean age 45.0±12.7 years) for four weeks. The primary endpoint was the change in cutaneous microcirculation blood flow before and after cold stimulation measured by laser Doppler imaging (LDI) at weeks 0 and 4. The frequency and severity of RP and the number of digital ulcers were also measured at weeks 0 and 4. The adverse events were recorded in the fourth week. ResultsThere was no significant change in digital blood flow assessed by LDI before or after cold stimulus after four weeks of NAC or placebo. Both groups showed significant improvement in the frequency and severity of RP attacks, with no difference between the two groups. At the end of the study, the placebo group had three digital ulcers, while the NAC group showed no ulcers. NAC was well tolerated and no patient discontinued the treatment. ConclusionsNAC orally at a dose of 1800mg/day showed no vasodilator effect on hands’ microcirculation after four weeks of treatment in patients with RP secondary to SSc.

N‐acetilcisteína oral no tratamento do fenômeno de Raynaud secundário à esclerose sistêmica: ensaio clínico randomizado, placebo‐controlado e duplo‐cego

ObjectiveTo evaluate the safety and efficacy of N‐acetylcysteine (NAC) orally on digital microcirculation blood flow in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). MethodsThis was a randomized, double‐blind, placebo‐controlled trial in which 42 patients with SSc received oral NAC at a dose of 600mg tid (21 patients, mean age 45.6±9.5 years) or placebo (21 patients, mean age 45.0±12.7 years) for four weeks. The primary endpoint was the change in cutaneous microcirculation blood flow before and after cold stimulation measured by laser Doppler imaging (LDI) at weeks 0 and 4. The frequency and severity of RP and the number of digital ulcers were also measured at weeks 0 and 4. The adverse events were recorded in the fourth week. ResultsThere was no significant change in digital blood flow assessed by LDI before or after cold stimulus after four weeks of NAC or placebo. Both groups showed significant improvement in the frequency and severity of RP attacks, with no difference between the two groups. At the end of the study, the placebo group had three digital ulcers, while the NAC group showed no ulcers. NAC was well tolerated and no patient discontinued the treatment. ConclusionsNAC orally at a dose of 1800mg/day showed no vasodilator effect on hands’ microcirculation after four weeks of treatment in patients with RP secondary to SSc.

AB0989 Uneven Temperature among Fingers after Cold-Water Immersion of Hands is A Useful Parameter to Identify Disturbed Peripheral Circulation in Patients with Raynaud Phenomenon

BackgroundPeripheral circulation is often disturbed in patients with connective tissue diseases (CTDs). Raynaud phenomenon (RP) is prevalent in and considerably characteristic of CTDs and we have long noticed colour unevenness...

Efficacy of bosentan in the treatment of Raynaud’s phenomenon in patients with systemic sclerosis never treated with prostanoids

The objective of this study was to evaluate the efficacy of the endothelin receptor antagonist, bosentan, in patients with Raynaud's phenomenon secondary to systemic sclerosis never treated with prostanoids and without digital ulcers. The study design is a preliminary, prospective open label trial. The patients recruited took one 62.5 mg dose of bosentan twice daily for 4 weeks, followed by 125 mg twice daily for 24 weeks. Of the 10 patients recruited, all completed the study. The reduction in Raynaud's phenomenon attacks at week 24 from the baseline was statistically significant (Δ-1.3, P=0.0126). The Raynaud's condition score showed a statistically significant improvement (Δ-1.4, P=0.0279), as did the visual analog pain scale (Δ-1.5, P=0.0016) at the 24th week. Bosentan appears to be effective and may be a valid alternative for the treatment of severe secondary Raynaud's phenomenon for patients where prostanoids therapy is contraindicated or refused.

Evaluation of Test Characteristics for Outcome Measures Used in Raynaud's Phenomenon Clinical Trials

Randomized controlled trials (RCTs) in Raynaud's phenomenon (RP) have shown conflicting efficacy data. Also, there is no consensus on the outcome measures that should be used. Our objectives were to assess the reliability of individual core set measures used in 3 RCTs, evaluate the placebo response for individual core set measures, and determine if a composite of individual core set measures will decrease the placebo response, which may improve our ability to see treatment effects in future trials. We analyzed core set measures from 249 patients in the placebo-treated groups from 3 RCTs. Core set measures analyzed included the Raynaud's Condition Score (RCS); patient and physician assessment of RP; pain, numbness, and tingling during an RP attack; average number of attacks/day; and duration of attacks. Intraclass correlation coefficients (ICCs) were calculated during the run-in period to the RCTs. ICCs of ≥0.70 were observed for the RCS, attack symptoms, and average attacks/day. A high placebo response rate was observed for all individual core measures except the duration of attacks. For the RCS, the placebo response ranged from 56% with ≥10% improvement to 19.5% with ≥60% improvement. In contrast, placebo response rates of 10-20% were observed when several core set measures were combined to develop a composite score. Outcome measures used in RCTs of RP are associated with marked variability. A combination of outcome measures is associated with low placebo responses. Future studies are needed to assess if a composite score will be able to differentiate placebo from an effective agent.

Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon: systematic review and meta-analysis of randomised trials

IntroductionRecent controlled trials have assessed the efficacy of phospodiesterase-5 (PDE-5) inhibitors in secondary Raynaud's phenomenon (RP). However, the conclusions are conflicting, and whether these drugs are effective remains unclear. The...