Abstract
Introduction
Raynaud’s phenomenon is episodic vasospasm of the peripheral vessels, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia, and, rarely, ulceration of the fingers and toes. It presents as episodic colour changes of the digits, usually in response to cold exposure or stress. The classic triphasic colour change is white (ischaemia), then blue (deoxygenation), then red (reperfusion). Raynaud’s phenomenon can be primary (idiopathic) or secondary to several different conditions and causes. This review deals with secondary Raynaud’s phenomenon.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of self-help measures for secondary Raynaud’s phenomenon? What are the effects of drug treatments for secondary Raynaud’s phenomenon? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: alpha-blockers; angiotensin-converting enzyme (ACE) inhibitors; angiotensin II receptor antagonists; antithrombotics/inhibitors of platelet aggregation; biofeedback; calcium channel blockers; endothelin-1 receptor antagonists; glyceryl trinitrate (transdermal); hand exercises; inositol nicotinate; moxisylyte; naftidrofuryl oxylate; phosphodiesterase inhibitors; prostaglandins (oral, intravenous); relaxation therapy; serotonin reuptake inhibitors (SRIs); smoking cessation; and warming hands and feet.
Key Points
Raynaud’s phenomenon is episodic vasospasm of the peripheral vessels, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia, and, rarely, ulceration of the fingers and toes.
It presents as episodic colour changes of the digits, usually in response to cold exposure or stress. The classic change is white (ischaemia), then blue (deoxygenation), then red (reperfusion).
Raynaud’s phenomenon can be primary (idiopathic) or secondary to several different conditions and causes. This review deals with secondary Raynaud’s phenomenon.
Most trials we found were in people with Raynaud's phenomenon secondary to systemic sclerosis.
We don't know whether biofeedback, hand exercises, relaxation therapy, smoking cessation, or warming hands and feet or keeping warm work, as we found no evidence.
Although we found no evidence, given the adverse effects of smoking on the vasculature, it is reasonable to encourage people with secondary Raynaud's to stop smoking.
Similarly, although we found no evidence, given that many people report exacerbation of symptoms in the cold, it is reasonable to avoid cold exposure and to keep the hands and feet warm if an attack develops.
Intravenous iloprost (a prostaglandin) reduces the frequency and severity of attacks compared with placebo in people with Raynaud's phenomenon secondary to systemic sclerosis.
Intravenous prostaglandins other than iloprost have been less well studied.
Calcium channel blockers (mainly nifedipine) may decrease the frequency and severity of vasospastic attacks over 2 weeks compared with placebo in people with Raynaud's phenomenon secondary to systemic sclerosis. However, evidence is limited.
Bosentan (a dual endothelin-1 receptor antagonist) may reduce new digital ulcer formation compared with placebo in people with Raynaud's phenomenon secondary to systemic sclerosis and with previous digital ulcers in the last 12 months. However, we found no evidence on bosentan in people with secondary Raynaud's without previous digital ulceration, so the results are not generalisable to all people with secondary Raynaud's.
We don't know whether naftidrofuryl oxalate, alpha-blockers, angiotensin II receptor antagonists, ACE inhibitors, antithrombotics/inhibitors of platelet aggregation, glyceryl trinitrate (transdermal), inositol nicotinate, moxisylyte, phosphodiesterase inhibitors, or SRIs work, as we found no evidence.
Oral prostaglandins are unlikely to be beneficial in people with secondary Raynaud's phenomenon.
About this condition
Definition
Raynaud's phenomenon is episodic vasospasm of the peripheral vessels, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia, and, rarely, ulceration of the fingers and toes. It presents as episodic colour changes of the digits, usually in response to cold exposure or stress. The classic triphasic colour change is white (ischaemia), then blue (deoxygenation), then red (reperfusion). Raynaud's phenomenon can be primary (idiopathic) or secondary to several different conditions or causes, including connective tissue diseases such as systemic sclerosis, extrinsic vascular obstruction (e.g., in thoracic outlet syndrome), certain drugs/chemicals (e.g., ergotamine, vinyl chloride), vibration exposure (hand-arm vibration syndrome), and hyperviscosity states. This review excludes primary (idiopathic) Raynaud's phenomenon, and concerns the management of secondary Raynaud’s phenomenon. Most of the evidence we found on secondary Raynaud's phenomenon was in people with systemic sclerosis.
Incidence/ Prevalence
See Raynaud's phenomenon (primary). The prevalence of secondary Raynaud's depends on the associated disease or condition. For example, the prevalence of Raynaud's phenomenon in people with systemic sclerosis is almost 100%.
Aetiology/ Risk factors
Many different conditions can be associated with secondary Raynaud’s phenomenon, and the pathogenesis and pathophysiology of Raynaud’s phenomenon vary depending upon these underlying conditions. Abnormalities of the blood vessel wall, of the neural control of vascular tone, and intravascular factors may all have a role. Other factors have also been implicated, including smoking (in people with systemic sclerosis, smoking is associated with severity of digital ischaemia), hormonal factors (Raynaud's is more common in women than in men), and genetic factors.
Prognosis
Secondary Raynaud’s phenomenon can be severe, and may progress to ulceration, scarring, and sometimes gangrene necessitating amputation. Therefore, prognosis depends, at least to some extent, on the underlying cause of Raynaud’s phenomenon. Prognosis has been studied best in people with systemic sclerosis who develop underlying structural vascular abnormalities affecting both the microcirculation and the digital arteries. One study found that, of 1168 people with systemic sclerosis, 203 people (17.4%) had severe digital vasculopathy (Raynaud's phenomenon complicated by digital ulceration, critical digital ischaemia, gangrene, or requiring digital sympathectomy).
Aims of intervention
To relieve or reduce the frequency and severity of Raynaud′s attacks, prevent tissue damage, preserve hand function, and improve quality of life, with minimal adverse effects of treatment.
Outcomes
Raynaud's attacks: frequency and duration of symptoms as assessed by patient diary; severity of symptoms assessed by patient diary or by visual analogue scales, Likert scales, or the Raynaud's Condition Score; Digital ulceration: rates, size and healing of digital ulceration; Hand function; Quality of life; and Adverse effects of treatment.
Methods
Clinical Evidence search and appraisal May 2007. The following databases were used to identify studies for this systematic review: Medline 1987 to May 2007 for systematic reviews and 1987 to July 2007 for RCTs and cohort studies, Embase 1987 to May 2007 for systematic reviews and 1987 to July 2007 for RCTs and cohort studies, and The Cochrane Database of Systematic Reviews Issue 2, 2007 and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 2. Additional searches used these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. We also searched for retractions of studies included in the reviews. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for evaluation in this review were: published systematic reviews and RCTs in any language, at least single blinded for drug interventions but including open studies for non-drug interventions, and containing 20 or more people, of whom more than 65% were followed up. In addition, we searched for prospective cohort studies for non-drug interventions. We included studies of people with primary Raynaud's if a subset of people with secondary Raynaud's could be separately identified and outcomes independently assessed, or if over 75% of people in the RCT had secondary Raynaud's. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. Most studies we found of treatment for secondary Raynaud's phenomenon were in people with systemic sclerosis. Difficulties in undertaking and interpreting clinical trials in people with Raynaud's phenomenon include the need to account for other extrinsic factors (e.g., symptoms may be worse over winter) and the need for an adequate comparison group (due to high rates of placebo response and the fluctuating nature of the disease). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Raynaud's phenomenon (secondary).
| Important outcomes | Digital ulceration, Hand function, Quality of life, Raynaud's attacks | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of drug treatments for secondary Raynaud's phenomenon? | |||||||||
| 1 (15) | Raynaud's attacks | Glyceryl trinitrate (transdermal) versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and methodological weaknesses |
| 8 (109) | Raynaud's attacks | Calcium channel blockers versus placebo | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and short follow-up. Directness point deducted for inclusion of people with primary Raynaud’s phenomenon |
| 1 (20) | Raynaud's attacks | Alpha-blockers versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (122) | Digital ulceration | Bosentan versus placebo | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness points deducted for uncertainty about generalisability of results in people without a history of digital ulceration and for co-intervention (vasodilators) |
| 22 (1) | Hand function | Bosentan versus placebo | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness points deducted for uncertainty about generalisability of results in people without a history of digital ulceration, and for co-intervention (vasodilators) |
| 1 (43) | Raynaud's attacks | Phosphodiesterase inhibitors versus placebo | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and for not specifying method of randomisation. Directness point deducted for inclusion of people with primary Raynaud’s disease |
| 5 (630) | Raynaud's attacks | Oral prostaglandins versus placebo | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| 2 (415) | Digital ulceration | Oral prostaglandins versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| At least 4 (At least 238) | Raynaud's attacks | Intravenous prostaglandins versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for heterogeneity among RCTs in analysis (one RCT assessed oral iloprost) |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Raynaud's phenomenon (primary)
Disclaimer
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