Raynaud\'s phenomenon (RP) is a cardinal feature of SSc and is associated with significant disease-related morbidity that impacts on quality of life. The assessment of SSc-RP is challenging. The aim of this scoping review was to evaluate the outcome domains studied and outcome measures used in clinical studies of SSc-RP.
Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials were used to identify randomized control trials (RCTs), quasi-randomized studies, case-control studies, prospective and retrospective cohort studies, case series, and cross-sectional studies of adult participants with SSc-associated RP, written in English. A minimum of 25 participants for studies of imaging modalities and 40 participants for questionnaire-based studies was required for inclusion. Basic laboratory and genetic studies were excluded. No limitations were imposed based on intervention, comparator, or study setting. Study characteristics and primary and secondary target domains in each study were recorded.
58 studies (24 randomized clinical trials) were included in the final analysis. The commonest domains captured were severity of attacks (n=35), frequency of attacks (n=28), and duration of attacks (n=19). Objective assessments of digital perfusion were also commonly used in studies of SSc-RP.
The outcome domains and the associated outcomes used to assess the impact of SSc-RP in research studies are broad and have varied across studies. The results of this study will inform the OMERACT Vascular Disease in Systemic Sclerosis Working Group to establish a core set of disease domains encompassing the impact of RP in SSc.

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

BACKGROUND: Methylphenidate (Ritalin) is a CNS stimulant, and is a common treatment for children and adults with ADHD. It has been associated with Raynaud\'s phenomenon (RP) but not with Systemic Sclerosis (SSc). We report a case series of patients pointing out the connection between Methylphenidate and SSc.
METHODS: We identified three patients in a single Rheumatology clinic in Israel, who developed SSc following treatment with CNS stimulants for ADHD. All three cases had Raynaud\'s phenomenon, skin changes, pathological capillaroscopy and positive ANA. Symptoms appeared and worsened over months following the use of methylphenidate and subsided after its cessation.
CONCLUSIONS: This is the first report in the literature of a causative relation between methylphenidate and the development of SSc, a serious, life-threatening condition. Patients treated with CNS stimulants should be followed closely for side-effects such as RP and skin changes.

Raynaud\'s phenomenon of the nipple is an unusual side-effect of labetalol use. There is one official report from the United Kingdom. The present case concerns a 30-year-old woman, gravida 1, para 0, who developed pre-eclampsia and was treated with labetalol but subsequently reported neuropathic pain of the nipple. Nifedipine was then started as part of her treatment plan for blood pressure control and she no longer reported pain, despite being given six more doses of labetalol. Nifedipine is the first-line of treatment for Raynaud\'s phenomenon. The concomitant use of labetalol with nifedipine by a woman with Raynaud\'s phenomenon of the nipple has not been discussed before. The goal of this review is to raise awareness of this drug-induced phenomenon and to add to the limited literature available on this subject.

Morphea profunda refers to inflammatory and sclerotic lesions that start primarily from the deep dermis, subcutaneous fat and fascia. Its pediatric case published work is limited. Here, we report the case of an 8-year-old girl with a 5-year history of multiple subcutaneous nodules on her extremities and a right wrist joint contracture who had been previously diagnosed with juvenile idiopathic arthritis and treated with salazosulfapyridine, low-dose prednisolone (PSL) and methotrexate. We performed biopsies of two subcutaneous nodules, which revealed the typical morphology of morphea profunda. She was administrated a tapered course of oral PSL then cyclosporin A (CyA) for 20 weeks which completely resolved her joint contracture and subcutaneous nodules. We reviewed 11 previously reported cases of morphea profunda and found that some include circumscribed/linear morphea that develop into subcutaneous tissues, indicating that \"classical\" morphea profunda arising within the deep tissues has rarely been reported. Our report is the first to demonstrate the efficacy of CyA for treatment of morphea profunda, and the possibility of CyA as a treatment option to reduce oral steroid doses in juvenile cases.

Objectives: Cold hypersensitivity in the hands and feet (CHHF) and Raynaud\'s phenomenon (RP) are prevalent among Asian populations, especially among women, who exhibit a higher rate of cold hypersensitivity that may be associated with gynecological problems. In several countries, herbal medicine has effectively treated cold hypersensitivity symptoms. This systematic review and meta-analysis of the literature was undertaken to evaluate the efficacy of herbal medicine for the treatment of CHHF in adults. Design: Through March 31, 2018, comprehensive databases were searched, including MEDLINE, EMBASE, Cochrane Library, Chinese Academic Journal, and Japanese National Institute of Informatics, to identify relevant studies and extract data. Outcome measures: Primary: total effective rate (TER); secondary: skin temperature, peripheral blood flow, adverse events. Results: Fourteen randomized controlled trials (n = 974) were included. Thirteen studies with dichotomous values showed a significant reduction in CHHF and RP (risk ratio 0.31, 0.24-0.40) when comparing herbal medicine with/without Western medicine, and no treatment or Western medicine alone. Reductions in CHHF and RP were also observed between herbal medicine plus Western medicine and Western medicine alone (risk ratio 0.45, 0.24-0.86), as well as between herbal medicine and Western medicine alone (risk ratio 0.30, 0.21-0.41). In the only study using a placebo arm, herbal medicine was found to be superior to placebo in increasing skin temperature and peripheral blood flow. Six participants exhibited minor adverse drug reactions. Herbal medicine showed a superior TER, especially when combined with Western medicine, to Western medicine alone or placebo. However, there was a high risk of bias within all studies. Conclusion: Although herbal medicine shows potential to be a safe and effective treatment for CHHF and RP, the high risk of bias in all studies prevents definitive conclusions; thus, higher quality studies must be performed.

BACKGROUND: Chemotherapy-induced skin sclerosis is generally not associated with other manifestations of systemic sclerosis. It is featured by skin sclerosis without visceral involvement (i.e., Raynaud\'s phenomenon, esophageal dysmotility, and pulmonary fibrosis), temporal association with chemotherapy administration, and the absence of detectable autoantibodies. The clinical course of scleroderma-like changes induced by paclitaxel or gemcitabine are refractory to treatment and commonly progressive, even after discontinuation of the triggering drugs.
OBJECTIVE: Report a case of scleroderma-like cutaneous lesions during combination treatment with nab-paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma and determine other published cases of scleroderma-like skin changes following treatment with nab-paclitaxel, paclitaxel, or gemcitabine through the period from 2002 to 2018.
METHODS: Literature search from the year 2002 onwards using combinations of \"Scleroderma\" AND \"paclitaxel,\" AND/OR \"gemcitabine.\"
RESULTS: Additional to our case report we reviewed 14 other cases in the literature. Most of these cases share three prominent features: skin sclerosis without systemic involvement, temporal association with chemotherapy administration, and absence of detectable scleroderma-specific autoantibodies.
CONCLUSIONS: To our knowledge, this is the first case report of scleroderma-like cutaneous lesions during combination treatment with nab-paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma. However, given the current literature, these scleroderma-like lesions are most likely induced by nab-paclitaxel or paclitaxel, rather than by gemcitabine.

BACKGROUND: Multiple placebo-controlled trials have assessed locally applied topical nitrate preparations in treating Raynaud\'s phenomenon (RP).
OBJECTIVE: The objective of this meta-analysis was to assess the effects of local topical nitrates in primary and secondary RP with respect to a combined end point integrating parameters of digital blood flow and clinical severity.
METHODS: A systematic review was performed using MEDLINE, Embase, and the Cochrane library. Only trials comparing locally applied topical nitrates with placebo comparators were included. Studies were appraised for bias by 2 independent reviewers.
RESULTS: A total of 7 placebo-controlled trials including 346 patients were used in the meta-analysis; 4 trials used nitroglycerin ointments, 2 used the nitroglycerin gel vehicle MQX-503, and 1 used compounded nitrite. The meta-analysis results supported a moderate-to-large treatment effect in RP (standardized mean difference [SMD] = 0.70; 95% CI, 0.35-1.05; P < .0001). Subgroup analyses showed a large treatment effect in secondary RP (SMD = 0.95; 95% CI, 0.25-1.65; P = .008) and moderate effect in primary RP (SMD = 0.45; 95% CI, 0.05-0.85; P = .03).
CONCLUSIONS: Limitations include the inclusion of multiple topical nitrate preparations and integration of different outcomes assessments.
CONCLUSIONS: Local topical nitrates have significant efficacy in the treatment of both primary and secondary RP.

BACKGROUND: Raynaud\'s phenomenon (RP) describes excessive peripheral vasospasm to cold exposure and/or emotional stress. RP episodes are associated with digital colour changes, pain and reduced quality of life. Pharmacological interventions are of low to moderate efficacy and often result in adverse effects such as facial flushing and headaches. Recommended lifestyle and behavioural interventions have not been evaluated. The objectives of the proposed systematic review are to assess the comparative safety and efficacy of behaviour change interventions for RP and identify what we can learn to inform future interventions.
UNASSIGNED: Studies eligible for inclusion include randomised controlled trials testing behaviour change interventions with a control comparator. A comprehensive search strategy will include peer review and grey literature up until 30 April 2017. Search databases will include Medline, Embase, PsychINFO and Cochrane. Initial sifting, eligibility, data extraction, risk of bias and quality assessment will be subject to review by two independent reviewers with a third reviewer resolving discrepancies. Risk of bias assessment will be performed using Cochrane risk of a bias assessment tool with quality of evidence assessed using Grading of Recommendations Assessment, Development and Evaluation(GRADE). A meta-analysis will be performed if there are sufficient data. Two subgroup analyses are planned: primary versus secondary RP outcomes; comparison of theoretically informed interventions with pragmatic interventions.
UNASSIGNED: This review does not require ethical approval as it will summarise published studies with non-identifiable data. This protocol complies with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. Findings will be disseminated in peer-reviewed articles and reported according to PRISMA. This review will make a significant contribution to the management of RP where no review of behaviour-change interventions currently exist. The synopsis and protocol for the proposed systematic review is registered in the International Prospective Register of Systematic Reviews (registration number CRD42017049643).