2016 Hughes Raynaud's Phenomenon

Best Practice & Research Clinical Rheumatology 30 (2016) 112e132
Contents lists available at ScienceDirect
Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh
Raynaud's phenomenon
Michael Hughes a, Ariane L. Herrick a, b, *
a
Centre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust,
Manchester Academic Health Science Centre, Manchester, UK
b
NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust,
Manchester Academic Health Science Centre, Manchester, UK
a b s t r a c t
Keywords:
Raynaud's phenomenon
Systemic sclerosis
Scleroderma
Connective tissue disease
Treatment
Digital ischaemia
Raynaud's phenomenon (RP) is a major cause of pain and disability

in patients with autoimmune connective tissue diseases (CTDs),
particularly systemic sclerosis (SSc). The clinician must perform a
comprehensive clinical assessment in patients with RP to differentiate between primary (idiopathic) and secondary RP, in
particular (for rheumatologists), secondary to an autoimmune
CTD, as both the prognosis and treatment may differ signicantly.
Key investigations are nailfold capillaroscopy and testing for autoantibodies (in particular, those associated with SSc). Patients
with RP and either abnormal nailfold capillaroscopy or an SScspecic antibody (and especially with both) have a high risk of
transitioning to an autoimmune CTD. Both nailfold capillaroscopy
and autoantibody specicity may help the clinician in predicting
organ-based complications. The management of CTD-associated
RP requires a multifaceted approach to treatment, including patient education and conservative (non-drug) measures. Patients
with CTD-associated RP often require pharmacological treatment,
which in the rst instance is usually a calcium channel blocker,
although other agents can be used. There is an increasing tendency
to use phosphodiesterase type 5 inhibitors early in the treatment
of CTD-associated RP. Oral therapies are commonly associated with
side effects (often due to systemic vasodilation) that may result in
failure of dose escalation and/or permanent discontinuation.
Intravenous prostanoid therapy and surgery (e.g., botulinum toxin
injection and digital sympathectomy) can be considered in severe
RP. Patients with CTD-associated RP can develop a number of
* Corresponding author. NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation
Trust, Manchester Academic Health Science Centre, Manchester, UK.
E-mail address: ariane.herrick@manchester.ac.uk (A.L. Herrick).
http://dx.doi.org/10.1016/j.berh.2016.04.001
1521-6942/ 2016 Published by Elsevier Ltd.
M. Hughes, A.L. Herrick / Best Practice & Research Clinical Rheumatology 30 (2016) 112e132
113
ischaemic digital complications (primarily ulcers and critical

ischaemia), which may be associated with signicant tissue loss.
Future research is required to increase the understanding of the
pathogenesis and natural history of RP (to drive therapeutic advances), and to explore/develop drug therapies, including those
that target the mechanisms mediating cold-induced vasoconstriction, and locally acting therapies free of systemic side effects.
2016 Published by Elsevier Ltd.
Introduction
Raynaud's phenomenon (RP) is common in patients with autoimmune connective tissue diseases
(CTDs) having a signicant impact on patients' perceived quality of life [1,2]. RP manifests as an
episodic colour change of the extremities, triggered by cold exposure and/or emotional stress. RP is
often one of the earliest clinical manifestations observed in patients with CTDs; thus, it presents an
early opportunity to identify patients likely to develop a CTD, in particular, systemic sclerosis (SSc). The
aim of this review is to provide an update on the assessment of patients with RP, the natural history of
CTD-associated RP and advances in therapies (including structured protocols) for RP and for the most
severe ischaemic complication critical digital ischaemia (treatment of SSc-related digital ulceration is
discussed in Chapter 1).
Assessment of the patient with RP
RP (Fig. 1) is common. The prevalence estimates vary, most likely reecting differences in denition
of RP between studies as well as geographic variations. One UK study suggested that the prevalence
could be as high as 19% [3], although most studies have suggested lower prevalences of 3e5% in the
general population [4].
The vast majority of patients presenting with RP will have primary (idiopathic) RP (PRP), which is
benign, in that it is entirely reversible and does not progress to irreversible tissue injury. However, the
clinician must bear in mind that RP has a differential diagnosis (Table 1). Although this includes a large
Fig. 1. Photographs of an RP attack taken by a patient with SSc using a smartphone camera. A: Whiteness (pallor of all four ngertips) is observed. B: The ngers return to their normal colour. The time between the two photographs was approximately two and
a half minutes. Photographs provided courtesy of Dr Graham Dinsdale, the University of Manchester.
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Table 1
The differential diagnosis of RP. Modied from Ref. [5].
Primary (idiopathic) RP
Secondary Vascular (usually proximal large vessel
RP
disease, often unilateral symptoms)
Compressive (e.g., cervical rib) Obstructive: non-inammatory

(i.e., atherosclerosis) Inammatory vascular disease (e.g.,
thromboangiitis obliterans (Buerger's disease))
Handearm vibration syndrome (vibration

white nger)
Autoimmune conditions
SSc
Systemic lupus erythematosus
gren's syndrome
Sjo
Mixed connective tissue disease/overlap syndromes
Undifferentiated connective tissue disease
Idiopathic inammatory myopathies
Drug-related
Amphetamines
Beta blockers
Bleomycin
Cisplatin
Clonidine
Cyclosporine
Interferon a and b
Methysergide
Polyvinyl chloride
Conditions associated with increased plasma Cryoglobulinaemia
viscosity and reduced digital perfusion
Cryobrinogenaemia
Paraproteinaemia
Malignancy (including as a paraneoplastic phenomenon)
Other causes and associations
Carpal tunnel syndrome
Frostbite
Hypothyroidism
number of different conditions including handearm vibration syndrome, extrinsic vascular

compression, intravascular diseases including paraproteinaemia and certain drug treatments
including beta-blockers [5], RP secondary to CTD is of utmost interest to the rheumatologist, which can
be very severe and difcult to treat. As already stated, RP is often one of the most visible and distressing
aspects of CTD, and can be the presenting feature.
When assessing a patient with RP, the key questions for the rheumatologist are as follows:
1. Why does this patient have RP? Could s/he have an underlying CTD?
2. How severe is the RP? This will dictate management. For example, mild RP may respond to conservative (non-drug) measures, whereas severe RP progressing to nger ulceration will require a
very aggressive approach.
As in most areas of medicine, a full assessment requires a detailed history and examination, complemented by targeted investigations. During the initial assessment, the clinician must be aware of the
proposed criteria for PRP [6], which have recently been revisited by Maverakis et al. [7] LeRoy and
Medger [6] proposed that for RP to be primary the following criteria must be met: the attacks of acral
pallor or cyanosis should be episodic; the peripheral pulses should be strong and symmetrical; there
should be no evidence of digital pitting, ulceration or gangrene; the nailfold capillaries should be
normal; and antinuclear antibody (ANA) should be negative/low titre and the erythrocyte sedimentation rate (ESR) normal. The criteria of Maverakis et al. do not require a normal ESR [7].
History and examination
Key points in the history are the presence of any symptoms pointing to an underlying CTD (e.g.,
photosensitivity or mouth ulcers) and/or symptoms indicating severe disease (e.g., interference with
activities of daily living or a history of digital ulcers). A full systems enquiry must therefore be taken,
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including a drug history, an occupational history (with particular reference to vibratory tool use or
chemical exposures) and a family history (specically of CTD).
Similarly, a full examination must be performed, but focussing specically on the ngers and toes,
for signs of digital ulceration, pitting scars, puffy ngers, sclerodactyly or any nailfold changes visible to
the naked eye. The peripheral pulses must be checked, to indicate proximal large vessel disease.
Investigations
The basic set of investigations comprises a blood count, ESR, ANA and nailfold capillaroscopy
(discussed below). The results of all tests should be normal/negative in PRP. Many clinicians consider a
blood biochemical prole with thyroid function tests and a thoracic outlet radiograph (looking for a
cervical rib) a part of the routine assessment. When the history and examination indicate an underlying CTD, tests for other autoantibodies (including disease-specic autoantibodies) should be
requested (the associations of RP with the different CTDs are discussed later). Other investigations
should be requested as clinically indicated [8]. For example, if large (proximal) vessel disease is suspected, then vascular investigations are indicated, initially with arterial Doppler studies.
SSc is the CTD most likely to be associated with the most severe RP, and most of the studies into
predictors of development of underlying CTD in patients with RP have been in the context of SSc. SScspecic autoantibodies (including anti-centromere and anti-topoisomerase (anti-Scl-70)) and nailfold
capillaroscopic abnormalities are now well recognised as independent risk factors for SSc [9].
Nailfold capillaroscopy
Normal nailfold capillaries (Fig. 2) are reassuring in patients with RP. Conversely, dilated loops, areas
of avascularity, distortion of the normal capillary architecture and multiple haemorrhages indicate an
underlying SSc-spectrum disorder [10]. The development and increasing availability of highmagnication videocapillarosopy (200e600), among other factors, have led to increased interest in
capillaroscopy in recent years [11]. Cutolo et al. described a method of scoring the scleroderma pattern
(early, active and late) [12]: the early pattern (especially relevant to an early diagnosis of an SScspectrum disorder in the patient presenting with RP) is characterised by the presence of a small
number of giant capillaries and of microhaemorrhages, without obvious capillary loss. Although
Fig. 2. Nailfold capillaroscopy. A: Normal capillaroscopy. The capillaries are regular (hairpin like) in appearance, which is reassuring
in patients with RP. B: Abnormal nailfold capillaroscopy in a patient with SSc. Several capillaries are enlarged, with areas of
avascularity.
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nailfold capillary abnormalities have been described in CTDs other than SSc, the changes tend to be
non-specic, other than in inammatory muscle disease (especially dermatomyositis (DM)), in which
scleroderma-pattern abnormalities are well described [13,14].
For clinicians without access to standard wide-eld microscopy or to videocapillaroscopy, capillaries may be visualised using a dermatoscope (magnication in the order of 10) [15,16] or with an
ophthalmoscope [16,17], although a disadvantage of the ophthalmoscope is the narrower eld of view.
A recent study [18] suggested that dermoscopy compared favourably to videocapillaroscopy; however,
videocapillaroscopy images were more likely to be classiable (and were graded more severely) than
dermoscopy images. It is likely that the USB microscope, a low-powered digital microscope that
connects to any computer via a USB port, will also be used in the future.
Although the main clinical indication for nailfold capillaroscopy is the diagnosis of underlying CTD,
recently, there has been considerable interest in capillaroscopy as a predictor of RP severity (specically
of digital ulceration) in patients with SSc [19e22].
Other vascular investigations
Infrared thermography measures surface temperature and can help differentiate between patients
with PRP and SSc [23] (Fig. 3). However, this is a relatively expensive technique available only in specialist
centres. Dynamic imaging, most commonly with a cold challenge test [24,25], is generally incorporated
into thermography protocols. The persistence of a temperature gradient along a nger of >1 C (ngertip
colder) at a room temperature of 30 C also helps differentiate PRP from SSc-related RP [23].
Fig. 3. Thermographic imaging of the hands during dynamic temperature challenge. Left column: thermal images at 23 C; middle
column: thermal images at 30 C; and right column: rewarming curves after cold challenge. At 23 C, the ngertips are cooler in
patients with both PRP and SRP (B and C), unlike in healthy controls in whom the ngertips are warm (A). At 30 C, unlike in PRP (D),
persistent temperature gradients (ngers cooler than the dorsum of the hand) are noted in SRP (E). Rewarming curves demonstrate
prompt rewarming in a healthy control subject (top), complete but delayed rewarming in a patient with PRP (middle) and no
rewarming in a patient with SSc (bottom). PRP: Primary Raynaud's phenomenon. SRP: Secondary Raynaud's phenomenon.
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A number of other methods have been applied in studies to differentiate between primary and SScrelated RP [26e28]. These include laser Doppler owmetry, laser Doppler imaging and laser speckle
contrast imaging [29,30], plethysmography and nger systolic pressure measurements [26]. These
methods have the potential to measure disease severity, but further validation is required before they
can become adopted as outcome measures.
RP in CTDs
RP is common in patients with autoimmune CTDs. In this section, we review the evidence relating to
the occurrence and clinical associates of RP in patients with CTDs, including the occurrence of digital
ischaemic complications, which, in part, inform the treatment of CTD-associated RP (discussed in the
third part of this review).
Systemic sclerosis
Almost all patients with SSc have RP, which is often the presenting feature. In an analysis of patients
from the European Scleroderma Trials and Research (EUSTAR) group, which included 7655 patients
with SSc, >95% of patients presented with a history of RP, with no difference observed between patients with limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) disease subtypes (96.6% and 96.1%,
respectively) [31]. Patients with lcSSc often present with a long history (often decades) of RP. In patients with dcSSc, however, the onset of RP typically occurs within a year (either before or after) of the
onset of skin sclerosis [32]. The importance of RP in patients with SSc is reected by its inclusion in the
2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classication criteria for SSc (scoring three points out of the nine required for the classication of SSc)
[33,34]. In addition, RP is one of only three key features or red ags (along with puffy ngers and ANA
positivity) that should alert the clinician to the Very Early Diagnosis of Systemic Sclerosis (VEDOSS)
cohort, requiring the presence of the SSc pattern on nailfold capillaroscopy or SSc-specic autoantibodies [35]. In an analysis of 469 patients with RP enrolled in the VEDOSS cohort [36], patients who
were ANA positive (compared to ANA negative) were more likely to show an SSc pattern on capillaroscopy (53.6% and 13.4%, respectively); in addition, vascular complications (telangiectasias, current
digital ulcers and pitting scars) were more common in ANA-positive RP patients. In patients with SSc,
RP is often very severe, which can progress to digital ulceration and sometimes to gangrene.
Mixed connective tissue disease
Similar to SSc, RP is very common in patients with mixed connective tissue disease (MCTD), the vast
majority of whom (in excess of 90%) will develop RP during the course of their disease [37]. In a study of
25 patients with MCTD, Sharp et al. reported that RP was present in 84% of patients [38]. A long history
of RP is often reported in patients with MCTD, and RP is often the only or one of few symptoms of a CTD
at the time of diagnosis [37]. In a longitudinal study, which included 47 patients with MCTD with a
mean follow-up period of 3e29 years, RP was present at the time of initial presentation, diagnosis and
cumulatively during follow-up in 74%, 89% and 96% of patients, respectively [37]. Digital ischaemic
complications including ulceration of the ngers are relatively rare compared to SSc [39]. More than
half of patients with MCTD may demonstrate a scleroderma pattern on nailfold capillaroscopy [40,41],
which has been reported to be associated with the development of internal organ complications [41].
Undifferentiated connective tissue disease
RP occurs in around half of patients with undifferentiated connective tissue disease (UCTD) [42,43].
In a retrospective study, which included 91 patients with a follow-up period of 1 year, the prevalence of
RP was reported to be 46% (second only to arthralgias at 80%) [42]. Similarly, De Angelis et al. reported
the prevalence of RP to be 52.5% in a study investigating the clinical and serological associates of RP in
patients with UCTD [43]. The patients with (vs. without) RP had a higher frequency of oesophageal
dysmotility and of anti-ribonucleoprotein antibodies. In addition, the authors reported that
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capillaroscopic abnormalities (in particular, widened and irregularly enlarged capillary loops) were
more often found in these patients with RP. The development of digital ischaemic lesions including
ulceration of the ngers should prompt the clinician to reassess the patient and consider the evolution
into a dened CTD, in particular SSc.
gren's syndrome
Sjo
gren's syndrome (SS), and up to one-third of
RP is commonly observed in patients with primary Sjo
patients may develop RP during the course of their disease [44e46]. In approximately half of patients
who develop RP, the onset of RP is reported before the onset of sicca symptoms, and often the frequency
of RP attacks either remains the same or decreases over the course of time [45]. Although an initial
association between HLA-DR3/4 and the presence of RP in patients with SS was reported [47], subsequent studies have not conrmed such an association [44,45,48]. Skopouli et al. reported that patients with SS with (vs. without) RP were more likely to develop glomerulonephritis, peripheral
neuropathy and myositis, although this did not reach statistical signicance [45]. No association between SS-associated autoantibody prole and RP has been reported [46]. Of mechanistic interest, an
association between the presence of anti-centromere antibody and RP has been reported in patients
with SS [49,50]. In a retrospective study, which included 535 patients with SS, the prevalence of anticentromere antibody was 3.7% [49]. Patients with SS and anti-centromere antibody positivity had a
higher prevalence of RP, but a lower prevalence of ocular dryness, hypergammaglobulinaemia and
anti-Ro and anti-La antibodies than those who were anti-centromere negative. Patients commonly
require pharmacological treatment for their RP, but digital ischaemic complications are rare. In a crosssectional study of 40 patients with SS-related RP, 15 (38%) patients required pharmacological treatment
for their RP, most commonly with calcium channel blockers, and one patient required intravenous
prostanoid therapy for digital ulcers and distal gangrene [46].
Systemic lupus erythematosus
The prevalence of RP in patients with systemic lupus erythematosus (SLE) has been reported to be
18e40% [51,52]. RP may develop prior to the diagnosis of SLE or during the course of the disease [52]. A
lower prevalence of RP has been reported in males [53,54] and in patients with late-onset SLE [55,56].
The presence of RP in patients with SLE is a potential clinical biomarker of internal organ complications.
In a study including 79 patients with SLE and RP, patients with (compared to those without) RP were
signicantly more likely to show central nervous system involvement and peripheral neuropathy,
whereas (secondary) SS was less common [52]. In their prospective study including 77 patients with
SLE, Kamel et al. reported that RP was associated with an increased risk of pulmonary hypertension
(relative risk 4.44), although this did not reach statistical signicance [57]. Although Vayssairat et al.
report an association between RP and anti-cardiolipin (IgG) antibody positivity in patients with SLE
[58], other authors have reported either a negative or no association with antiphospholipid (IgG and
IgM anti-cardiolipin and anti-beta 2 glycoprotein) antibodies [59,60]. A positive association between
RP and anti-RNP antibody in patients with SLE has been reported [51]. Rodriguez et al. report that
patients with SLE and RP are likely to develop both arterial and venous thromboses in the presence of
anti-cardiolipin antibodies, although this did not reach statistical signicance [61]. SSc-like nailfold
capillaroscopic abnormalities have been associated with RP in patients with SLE [62].
Idiopathic inammatory myopathies
RP is not uncommon in patients with idiopathic inammatory myopathies (IIMs), particularly in
patients with anti-synthetase syndrome. In a study from a large, unselected Norwegian cohort of 230
patients with IIMs, the frequency of RP was found to be around 20% in polymyositis and 40% in DM [63].
The anti-synthetase syndrome is a clinical subset of IIMs including interstitial lung disease (ILD),
cutaneous features, RP and the presence of autoantibodies directed towards aminoacyl-transfer RNA
(tRNA) synthetases [64]. In their review on the anti-synthetase syndrome, Katzap et al. reported the
incidence of RP to be as high as 62% [64]. In a study including 41 patients with IIMs, only patients with
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(vs. without) anti-Jo-1 antibodies had RP (42% and 0%, respectively) [65]. Anti-melanoma differentiation-associated gene-5 (MDA5) antibody is signicantly associated with the development of cutaneous ulceration (and also ILD) in patients with DM [66]. In a retrospective study, which included 152
patients with DM, 43 patients (28%) presented with cutaneous ulcers [66]. The pathophysiology of
cutaneous ulceration in IIMs warrants further investigation.
Transition from primary to secondary RD
As previously described, the distinction between primary and secondary RP (PRP and SRP) is of
great importance, as both the prognosis and treatment can differ signicantly. In the literature, between 1% and 3% of patients with isolated PRP have been reported to evolve into SRP every year
[67,68], often within 5 years from the rst assessment [67,69,70].
As highlighted in the assessment of RP, nailfold capillaroscopy and testing for autoantibodies e in
particular, SSc-associated autoantibodies e are key investigations in patients with RP. In a large, prospective study that included 586 patients who were followed up for 3197 person-years, 12.6% of patients progressed to SSc [9]. The time to develop SSc after the rst evaluation and the rst onset of RP
was 1.95 and 4.56 years, respectively. In the patients who developed SSc, the frequency of nailfold
capillary abnormalities and SSc autoantibodies was 58% and 78.4%, respectively, and the presence of
both was associated with a 60-fold increased risk of developing SSc. Of interest, a different temporal
relationship for the development of microvascular damage (as assessed by capillary enlargement on
capillaroscopy) was observed between different autoantibodies (earliest with anti-RNA polymerase,
intermediate with anti-topoisomerase and latest with anti-centromere). In a systematic review and
meta-analysis, which included 639 patients with PRP (with a follow-up period of 2531 patient-years),
12.6% of patients developed SRP over an average follow-up duration of 4 years [67]. The adjusted odds
ratio (OR) of predictors of progression to SRP included the presence of abnormal nailfold capillaries
(14.6) and ANA positivity (3.0). Ingegnoli et al. proposed a simple prognostic algorithm to predict the
probability (10%, 10e50% and 50%) of patients with isolated RP developing SSc based on the
number of nailfold capillaries, presence of giant loops and ANA positivity, with good reported prognostic discriminatory ability (Harrell's C-index 0.86) [71]. Furthermore, in a prospective study
including 307 consecutive patients with RP, in addition to ANA positivity, other predictors (hazard
ratio) of transition to SRP were older age at the time of RP onset (2.59), shorter RP duration (0.87) and
abnormal thoracic outlet testing [68].
Just as in adults, nailfold capillaroscopy is a very useful prognostic tool for the development of an
autoimmune CTD in the juvenile population as well. In a prospective study that included 250 children
and adolescents (with a mean age of 15 years) with RP, 23.6% had developed a CTD at the end of followup (ranging between 1 and 6 years) [72]. Although most individuals who developed a CTD showed
normal capillaries or non-specic abnormalities on capillaroscopy, the presence of the scleroderma
pattern on capillaroscopy was found in more than half (61%) of the individuals who developed an SSc
spectrum disorder 6 months before the full expression of their CTD.
Another key issue operationally is the denition of the transition from PRP to SRP, including the
development of autoimmune CTDs, in particular SSc, in their earliest forms. In a study including 129
patients referred with PRP, Cutolo et al. reported that 14.7% (19 patients) developed SRP, dened by
the presence of abnormal nailfold capillaroscopy, over a mean follow-up period of 29.4 months [73].
The importance of nailfold capillaroscopy and SSc-associated autoantibodies in the early diagnosis of
SSc is reected in the inclusion of these investigations in the 2013 ACR/EULAR classication criteria
for SSc [33,34], as well as the VEDOSS criteria [35]. When the presence of an underlying CTD in the
patient presenting with RP is uncertain, many clinicians will adopt a pragmatic approach if there are
any abnormalities suggestive (but not diagnostic) of an underlying CTD (e.g., a weakly positive ANA
and borderline widened capillaries) and repeat the capillaroscopy in 6e12 months. Cutolo et al.
proposed twice-yearly capillaroscopic examination of patients with PRP in order to detect the
transition to SRP at the earliest opportunity [73]. From the available data, it would seem reasonable
to keep particularly patients at the highest risk of developing SRP under (at least) annual review for
up to 5 years (as the majority of patients could be expected to transition to SRP during this time
period).
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Future prospective, longitudinal studies are required to further understand the transition from PRP
to SRP, with a view to devising possible early intervention strategies (e.g., vascular remodelling agents)
and to informing the optimal treatment of RP at different stages of the disease process. A key issue in
future studies is how RP attacks (both frequency and severity) are measured. The current methods are
subjective and are often based on successful patient diary completion and return (these diaries are not
always returned). Possible approaches to overcome these issues would be developing a uniform
denition of RP and developing novel methods of measuring RP (e.g., objective vascular imaging and
mobile smartphone technology).
Treatment of RP
This section provides the reader with a useful clinical overview of the range of treatment options for
patients with CTD-associated RP. Although we consider the treatment of RP under four distinct categories e general approach to treatment, uncomplicated RP, other drug therapies and surgical
strategies e it is important to recognise that patients may need treatments from across these (e.g., in
the event of treatment failure and the development of ischaemic digital complications). This review
focusses on the treatment of SSc-associated RP, because the majority of the evidence has been obtained
for the treatment of CTD-associated RP. Although a wide range of drug treatments for RP has been
explored, this review focusses on those most commonly used by clinicians, and those (including those
of mechanistic value) warranting future research.
It is worth noting that in patients with autoimmune CTDs, RP is part of a spectrum of digital vascular
diseases (along with digital ulcers and critical ischaemia), which includes other organ-based vascular
complications (e.g., pulmonary arterial hypertension). Therefore, the therapeutic rationale for CTDassociated RP treatment should be made on an individual patient basis, considering his/her disease
severity. As the management of digital ulcers is described in Chapter 1, it is not discussed here.
However, here, we consider the (limited) evidence on the management of critical digital ischaemia (in
patients with SSc).
The UK Scleroderma Study Group has produced a number of treatment algorithms that aim to
provide the clinician with accessible reference tools for use in the daily management of patients with
SSc and digital vasculopathy: RP (Fig. 4), digital ulcers and critical digital ischaemia (Fig. 5) [74].
General approach to treatment of RP
The treatment of CTD-associated RP should be based on a detailed clinical assessment, including
investigating the impact of RP on patients' quality of life. General and lifestyle adaptations are rst line
in the management of all patients with RP, irrespective of the underlying aetiology. Patient education is
a key component, which ideally should be delivered by a dedicated, multidisciplinary team including
specialist nursing input. Patients should be encouraged to keep warm (e.g., by wearing multiple layers
of clothing and by using hand warmers/gloves) and to avoid cold ambient environments and/or
emotional stressors. Some patients nd that running their hands under warm water or moving their
arms in a circular motion can help reduce the severity and/or duration of RP attacks. Patients should be
offered contact information about national RP organisations, which are a great source of information
and support for patients with RP.
Patients should be counselled about the importance of quitting smoking (which promotes vasoconstriction) and be given adequate support to quit smoking. Patients with SSc who smoke (compared
to those who do not) have more severe digital vascular disease [75,76]. In a study that included 101
patients with SSc, current smokers (compared to those who had never smoked) were signicantly
more likely (OR) to have undergone surgical debridement (OR 4.5) or to have had received intravenous
vasodilator therapy (OR 3.8) [75]. Many patients prefer complementary and alternative therapies
including (but not limited to) acupuncture, biofeedback, gamolenic acid, gingko biloba and vitamins C
and E; however, at present, there is little evidence to support these interventions. Moreover, of
concern, these may have potentially hazardous pharmacological interactions with the prescribed
medications.
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Fig. 4. The management of RP in patients with SSc. From the UK Scleroderma Study Group consensus best practice pathway of the
UK Systemic Sclerosis: Digital vasculopathy in SSc. ACE: angiotensin-converting enzyme. ARB: Angiotensin receptor blocker. CCB:
calcium channel blocker. IV: intravenous. PDE-5: phosphodiesterase type 5. SSRI: Selective serotonin receptor inhibitor. Reproduced
with permission of the copyright owner [74].
Uncomplicated RP
Uncomplicated RP refers to RP in the absence of irreversible ischaemic tissue loss (i.e., digital
pitting scars, ulcers and critical ischaemia) (Fig. 6). In uncomplicated RP due to CTDs, especially in
patients with SSc (in whom RP is in part due to progressive, obliterative vasculopathy), drug treatment
is often indicated.
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Fig. 5. The management of critical digital ischaemia in patients with SSc. From the UK Scleroderma Study Group consensus best
practice pathway of the UK Systemic Sclerosis: Digital vasculopathy in SSc. IV: intravenous. PDE-5: phosphodiesterase type 5.
Reproduced with permission of the copyright owner [74].
As a general rule, drug therapies are usually started at the lowest possible dose and gradually
increased if not efcacious and in the absence of signicant side effects, which would require dose
reduction and/or discontinuation. Patients often tolerate longer-acting preparations of vasodilatory
drug therapies such as calcium channel blockers (CCBs) than the shorter-acting preparations. After
failure of any one drug, the introduction of another agent can be considered (either in combination
with the existing agent, if some albeit minimal benet was found, or as a substitution). No evidence has
been obtained from randomised controlled trials to guide clinicians on combination therapy in RP.
Thus, research is needed in this area.
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Fig. 6. Digital vascular disease in CTD-associated RP. Digital pitting (A), ulceration (B) and critical ischaemia (C) in patients with SSc.
Calcium channel blockers

Oral dihydropyridine CCBs, in particular nifedipine, are considered by many clinicians to be the
rst-line drug for all patients with RP, an approach supported by the EULAR recommendations for the
treatment of SSc [77]. In a meta-analysis including eight randomised controlled trials (with 109 patients with SSc), treatment with CCBs was associated with a signicant reduction in both the frequency
(mean reduction of 8.3 attacks over 2 weeks) and severity of RP attacks (35% reduced severity) [78].
Non-dihydropyridine therapy (e.g., diltiazem) can be considered if the patient is intolerant of dihydropyridine CCBs, or in the case of another specic indication (e.g., cardiac arrhythmia). CCB therapy is
commonly associated with side effects, including (but not limited to) headache, facial ushing, ankle
swelling and systemic hypotension (including orthostatic symptoms).
Angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists
A strong mechanistic rationale has been proposed for targeting the renineangiotensin system in the
treatment of CTD-associated RP. For example, angiotensin-II is a potent vasoconstrictor, and
angiotensin-converting enzyme (ACE) inhibitors are widely used in patients with ischaemic heart
disease to prevent the detrimental brotic remodelling of infarcted myocardial tissue.
However, the evidence for the use of ACE inhibitors for RP is limited and conicting, with little
evidence to suggest any benecial effect [79]. The largest (and most recent) study was a multicentre,
double-blind, randomised, placebo-controlled trial, which included 210 patients with lcSSc or RP and
an SSc-associated autoantibody [80]. Treatment with quinapril over 2e3 years was not associated with
a signicant improvement in RP (either the frequency or severity of attacks) or in other vascular
complications (including digital ulcers).
A number of clinicians favour angiotensin-II receptor blockade for the treatment of RP, either in
combination with, or after failure of, CCB therapy. In a single centre, parallel-group, open-label trial,
which included 52 (27 with SSc) patients with RP, despite a reduction in RP severity with both losartan
and nifedipine, the effect was greater in the losartan arm, and RP frequency was only reduced with
losartan [81].
Supplementation of the L-arginine/nitric oxide pathway
Nitric oxide (NO) is a ubiquitous molecule with a wide range of biological activities, including potent
vasodilation. NO is synthesised in endothelial cells from L-arginine by the action of (endothelial) NO
synthase. Subsequently, it acts as a secondary messenger in smooth muscle cells, via its action on
soluble guanylate cyclase and conversion of adenosine triphosphate (ATP) to cyclic guanosine monophosphate (cGMP), promoting marked smooth muscle relaxation [82]. Glyceryl trinitrate (GTN) is a
direct NO donor, whereas phosphodiesterase type 5 (PDE-5) inhibitors prevent the degradation (and
therefore local bioavailability) of NO by inhibiting cGMP breakdown.
Various forms of nitrate therapy have been explored in the treatment of RP (e.g., topical ointments
and sustained-release patches) [83,84]. However, these have often been associated with intolerable
adverse effects relating to systemic vasodilation, which have limited their clinical applicability. Topical
GTN increases perfusion in intact skin in patients, including patients with SSc [85]. Although treatment
124
with sustained-released transdermal patches was associated with a reduction in the number and
severity of RP attacks (including in patients with SSc) in a randomised, double-blind, placebocontrolled, crossover study including 42 patients (including 21 with SSc), adverse effects were common, in particular headaches, which led to eight patients discontinuing the study (and affecting 80% of
the remaining patients) [83].
As a locally acting treatment, topical GTN has been increasingly studied as a treatment for RP. MQX503 is a novel topical preparation of GTN [84]. In a multicentre, double-blind, randomised, placebocontrolled trial, 4 weeks after a 2-week, single-blind, placebo run-in period, treatment with MCQ503 gel (applied immediately before or within 5 min of a RP attack) was associated with a signicant improvement in patients' Raynaud's condition score (RCS) compared to placebo (0.48 and 0.04,
respectively), but not in the frequency or duration of RP attacks [84]. In a subsequently published
laboratory-based multicentre, double-blind, randomised, controlled, crossover study, the time taken to
recover from cold exposure was signicantly shorter, and the proportion who achieved baseline blood
ow higher, among those being treated with topical MQX-503 [86].
A number of PDE-5 inhibitors (sildenal, tadalal, vardenal and udenal) have been investigated
in the treatment of RP to date [87,88]; despite initially conicting results, the more recent studies have
suggested an improvement in RP with PDE-5 inhibitors [89e91]. Longer-term trials are needed to
conrm these ndings, because the studies to date have been of short duration (the longest treatment
phase being 8 weeks) [89]. PDE-5 inhibitors are likely to be used earlier in the treatment of RP, probably
after treatment failure with CCBs. In a meta-analysis including six RCTs (two sildenal (including one
modied-release sildenal), three tadalal and 1 vardenal), PDE-5 inhibition was associated with a
signicant decrease in the mean RCS (0.46) and daily frequency and duration of RP attacks (0.49
attacks and 14.62 min, respectively) [87]. The role of PDE-5 inhibition in the treatment (in particular,
healing) of digital ulcers has been previously discussed in Chapter 1.
Prostanoids
Intravenous prostanoids (prostacyclins and analogues) are indicated in patients with severe RP,
that is, in patients who develop ischaemic digital complications (ulceration and critical ischaemia).
However, prostanoids are occasionally used in uncomplicated CTD-associated RP, which has a signicant impact on patients' quality of life, and is refractory to the previously described measures.
Prostanoids may be administered by several routes, including the oral and intravenous routes. Oral
prostanoids are often poorly tolerated, with little or no signicant benet on RP [92]. Commonly
prescribed intravenous prostanoids include iloprost and epoprostenol, and the choice of drug often
depends on the prevailing prescribing restrictions between countries (e.g., intravenous epoprostenol,
but not iloprost, is available in the United States).
Intravenous iloprost is typically administered for a course of 3e5 consecutive days, at a (continuous)
dose of 0.5e2.0 ng/kg/min (titrated to the maximum tolerated dose by the patient) [93]. In a multicentre,
randomised, parallel-group, placebo-controlled, double-blind study by Wigley et al., among 126 patients
who completed the described treatment protocol, intravenous iloprost compared to placebo was associated with a mean reduction in the number of weekly RP attacks (39.1% vs. 22.2%) and an improvement
in the global Raynaud severity score (34.8% vs. 19.7%) during the 9-week follow-up period [93]. The
Raynaud's severity score used [93] was similar but not identical to the RCS. In a randomised, doubleblind, placebo-controlled trial including 14 patients with RP (eight with a CTD), treatment with intravenous epoprostenol (weekly infusions for 3 weeks, at a rate of 7.5 ng/kg/min after the rst hour for a
duration of 5 h) was associated with a signicant reduction in the frequency and duration of RP attacks,
with a loss in clinical response observed between 8 and 10 weeks after the last infusion [94].
Alpha-adrenergic receptor blockade
The evidence to support the use of alpha-adrenergic-blocking drugs (e.g., prazosin) in RP is limited
at best. In a Cochrane review including two randomised controlled crossover trials (with a total of 40
patients with SSc), treatment with prazosin for 6 weeks was only found to be fairly more effective than
placebo in reducing the frequency and duration, but not the severity, of RP attacks [95]. In addition,
treatment with prazosin was commonly associated with adverse effects, which needs to be balanced
against the apparently modest clinical benet.
125
Serotonin-targeting therapies
Platelet serotonin (5-hydroxytryptamine) has been implicated in the pathogenesis of RP and has been
investigated as a target for the treatment of RP, including selective serotonin reuptake inhibitors (SSRIs)
such as uoxetine [96]. Fluoxetine is widely available, which is prescribed for patients who are particularly prone to systemic vasodilatory adverse effects [74]. In a randomised, open-label, crossover study
that included 26 and 27 patients with PRP and SRP, respectively, 6 weeks of treatment with either
uoxetine or nifedipine was associated with a reduction in both the frequency and severity of attacks of
RP in both groups; however, the effect was only statistically signicant in the uoxetine-treated arm [96].
What is the evidence for and role of ERA (endothelial receptor antagonists)?
Data supporting the use of endothelial receptor antagonists (e.g., bosentan) for the treatment of
CTD-associated RP are lacking.
Other drug therapies with benets in patients with RP
Statins
Statin (3-hydroxy-3-methyl-glutarylecoenzyme A reductase (HMGeCoA reductase)) therapy is
considered to have benecial effects on the cardiovascular system independently of a lipid-lowering
effect, including (but not limited to) increased NO bioavailability and improvement in endothelial
function, favourable modulation of the immune system and brotic response and increased numbers of
endothelial progenitor cells [97e99].
In a double-blind, randomised, placebo-controlled trial, which included 84 patients with SSc, a
greater reduction in RP severity (visual analogue scale ((VAS)), 0e10) was seen in patients treated
(40 mg daily) with atorvastatin (6.0 vs. 4.9) for 4 months than those treated with the placebo (6.0 vs.
5.8) (P 0.005) [97]. By contrast, in a randomised, parallel-group, double-blind study examining the
microvasculature in patients with SSc, which included 36 patients with SSc, atorvastatin (20 mg daily)
was not associated with any signicant improvement (apart from a reduction in serum cholesterol) in
any outcome measure, including endothelial-dependent vasodilation (the primary end point of the
study) compared to placebo [100]. In a recent literature review on the effects of statins in SSc, which
included 18 relevant studies, improvement in RP (as assessed by VAS) was noted in four out of six
studies [99]. The authors concluded that, in general, the literature conrms that the treatment is safe
and well tolerated (with promising data regarding certain vascular outcomes, e.g., digital ulcers), and
they highlighted the need for future research (namely, randomised clinical trials) into this area [99].
Antiplatelet therapy and anticoagulation
Although there is a strong rationale for antiplatelet therapy and anticoagulation (e.g., platelet
activation and proliferative microvascular obliteration) in CTD-associated RP, especially in patients
with digital ulcers and critical ischaemia, the evidence for these interventions is limited (and likely to
be in future as well). Antiplatelet and anticoagulant therapies are potentially hazardous (even life
threatening) particularly in SSc, as many patients are prone to show bleeding from the gastrointestinal
tract (e.g., from gastric antral vascular ectasia). Therefore, the potential benets of such agents should
be balanced against the potential risks in an individual patient.
In a randomised, double-blind, controlled trial, which included 28 patients with early SSc, highdose dual antiplatelet therapy with aspirin (975 mg) and dipyridamole (225 mg) was not associated
with any signicant improvement in RP after a maximum of 2 years of treatment [101]. In a prospective, parallel-group study, which included 30 patients with SSc, treatment with low molecular
weight heparin for 24 weeks was associated with a signicant reduction in Raynaud's severity score
(from baseline) compared to patients in the matched control group (1.9 and 0.4, respectively;
P 0.0002) [102]. No studies have been conducted on the newer anticoagulants (e.g., direct thrombin
inhibitors); thus, further research into this area could be considered.
Antioxidants
Oxidative stress has been implicated in the pathogenesis of SSc [5]. However, the evidence to
support the use of antioxidants in SSc-associated RP is limited and conicting. In a multicentre, open-
126
label trial, which included 22 patients with SSc and RP, treatment with intravenous N-acetylcysteine
(NAC) was reported to be safe and well tolerated, related to a signicant reduction in both the frequency and severity of RP attacks [103]. However, in a recent randomised, double-blind, placebocontrolled clinical trial, Correa et al. found no difference in either the response to cold challenge as
assessed by laser Doppler imaging (the primary end point of the study) or the frequency or severity of
RP attacks after 4 weeks of treatment with oral NAC [104]. In addition, treatment with a combination of
micronutrient antioxidants (selenium, beta-carotene, vitamins C and E and methionine) and allopurinol in a 20-week double-blind, crossover trial in 33 patients with lcSSc was not associated with any
clinical benet when compared to placebo [105]. Further research is warranted to investigate the role
of antioxidant therapy in RP.
Inhibition of cold-induced vasoconstriction
Signicant advances have been made in elucidating the physiological mechanisms mediating coldinduced vasoconstriction, in particular the Rho/RhoA kinase signalling pathway and the role of vascular
smooth muscle cell alpha2c-adrenoreceptors [106]. In two small single-centre, double-blind, placebocontrolled, randomised studies, neither oral fasudil (Rho kinase inhibitor) nor ORM-12741 (alpha2cadrenoceptor antagonist) was associated with objective vascular improvement (after a cold challenge)
[107,108]. However, further research is warranted in this area, as inhibition of cold sensitivity is a
promising target in RP.
Immunosuppression
Currently, evidence to support the use of immunosuppressive therapy in CTD-associated RP is
limited; however, this may be re-examined in the future with new insights into the pathogenesis of the
autoimmune CTDs, for example, if an inammatory drive (which, if present, may be dependent on the
disease stage) to the vascular components of these conditions is found.
Surgery
Surgical intervention should be considered in patients with RP refractory to the previously
described interventions and/or in the presence of ischaemic digital complications (i.e., ulcers and
critical ischaemia). Patients with SSc may have an increased risk of macrovascular disease. The possibility of proximal (large) vessel disease [109,110] should be considered, particularly in patients with
asymmetrical digital vascular disease, as this may be amenable to revascularisation therapies.
Cervical sympathectomy is no longer indicated for the treatment of RP: patients often presented
with recurring symptoms, including possible worsening of RP, often within a few months of surgery
[111]. Injections of botulinum toxin and digital (palmar) sympathectomy have been increasingly
considered in patients with RP, especially patients with digital ulcers and critical digital ischaemia,
although the evidence to support these interventions at present is limited [112].
Botulinum toxin is produced by the bacterium Clostridium botulinum. Although the mechanism of
action in RP is incompletely understood currently, it is likely to include blockade across the neuromuscular end plate with inhibition of smooth muscle vasoconstriction [113]. Several authors have
reported an improvement in RP (and digital ulcer healing) after injections of botulinum toxin
[113e115]. Of note, in a systematic review of ve studies, botulinum toxin injection was associated with
clinical improvement in RP, although the authors highlighted the signicant limitations of these
studies (e.g., differences in the patient characteristics and the injection technique used) and the need
for a randomised controlled trial in this area [113].
Digital sympathectomy should be considered in patients with refractory and/or recurrent digital
ulcers [116e118]. A systematic review (which included 16 studies of 43 patients, 34 of whom had SSc)
described the outcomes of digital sympathectomy for the treatment of critical digital ischaemia; where
available, ulcer healing ranged between 2 weeks and 7 months [117]. However, recurrence of ulceration
and the need for amputation were not completely avoided post sympathectomy (18% and 14%,
respectively). Momeni et al. recommended offering digital sympathectomy earlier in the disease
127
process (in patients with SSc) to accelerate ulcer healing, and to reduce the duration of pain experienced by patients [118].
Fat transplantation is also currently being considered for the treatment of RP. It has been reported to
be associated with improvement in RP and digital ulcer healing [119], and further research is warranted
on this technique.
Critical digital ischaemia
Critical digital ischaemia (along with digital ulcers) represents the most severe end of the spectrum
of digital vascular disease observed in patients with RP, particularly in SSc. Critical digital ischaemia is
a true medical emergency, and all patients with RP should be counselled to seek urgent medical
attention if any of the digits becomes permanently discoloured. In a large retrospective study (which
included 1168 patients with SSc) from the Royal Free Hospital, London, during 18 months of follow-up,
19 (1.6%) and 16 (1.4%) of patients developed critical digital ischaemia or gangrene, respectively, often
resulting in loss of the digit (either by autoamputation or surgical amputation) [120]. Both anticentromere and anti-b2-glycoprotein antibodies have been associated with critical digital
ischaemia in patients with SSc [121,122]. Smoking is a risk factor for more severe digital vascular
disease in SSc. As previously described, patients with SSc may be at an increased risk of macrovascular
disease; therefore, the peripheral pulses must always be examined. If there is ongoing concern,
vascular imaging (with Doppler arterial ultrasound in the rst instance) should be performed early in
patients with critical digital ischaemia to exclude signicant large vessel disease. In patients with
autoimmune CTDs, the clinician must remain vigilant and consider the range of other causes of critical
digital ischaemia, including (but not limited to) thromboembolic disease, a tendency towards
thrombosis, vasculitis, paraproteinaemia and cryoglobulinaemia and ischaemia occurring as a paraneoplastic phenomenon.
The evidence for guiding the management of critical digital ischaemia in autoimmune CTDs is
lacking at present. Therefore, as a generalisation, the management of patients presenting with
ischaemia is similar to those patients without an underlying rheumatological condition. Patients
should be admitted on an emergency basis and their analgesic regimen reviewed and optimised early
during the course of their admission, who often require opioid-based pain control. Critically ischaemic
digits are often infected, and clinicians should have a low threshold to prescribe appropriate (often
intravenous) antibiotic therapy, as per local standard practice of prescribing antibiotics. Many clinicians
consider antiplatelet therapy and anticoagulation in patients with critical digital ischaemia. Patients
are often prescribed intravenous prostanoid therapy, in an attempt to save the digit. In patients with an
associated vasculitic process, for example, in patients with SLE or pSS, steroid and/or immunosuppressant therapy should be considered.
The critically ischaemic digit often will spontaneously autoamputate (commonly with an
improvement in pain); however, surgical debridement and/or amputation of necrotic tissue may be
required, including for cosmesis. Botulinum toxin injection and digital sympathectomy may be
considered in patients with critical digital ischaemia, although the evidence to support this intervention is limited at present.
Conclusion
In conclusion, RP is common in patients with autoimmune CTDs, leading to considerable pain and
disability. The clinician must perform a comprehensive clinical assessment with targeted investigations to distinguish between PRP and SRP, as both the prognosis and treatment may differ
signicantly (e.g., SRP is often more severe and requires intensive drug dose escalation and/or change
in therapy). Key investigations in the assessment of patients with RP include autoantibody testing (in
particular, autoantibodies associated with SSc) and nailfold capillaroscopy. These are both included in
the ACR/EULAR 2013 SSc classication criteria. They are also useful clinically to help identify patients
who are likely to have a more severe disease course. The treatment of CTD-associated RP is multifaceted and should be delivered by a dedicated multidisciplinary team. Despite conservative measures,
many patients require drug therapy. Patients with CTD-associated RP, in particular SSc, may develop a
128
spectrum of serious digital vascular diseases including ulcers and critical ischaemia, which can result in
loss of digits. Future research is needed to better understand the pathogenesis of RP (including in CTDs)
including prospective studies of transition to SRP, to explore drug therapies (including those with a
poor evidence base) and novel therapeutic targets (e.g., inhibition of cold-induced vasoconstriction),
and to delineate the role (and timing) of advanced surgical procedures.
Practice points
RP is common and often one of the earliest clinical manifestations in patients with autoimmune CTDs.
The clinician must perform a comprehensive clinical assessment in order to identify patients
with secondary RP.
Key investigations to identify secondary RP include capillaroscopy and testing for autoantibodies, which have been found to have a predictive role in the risk stratification of patients.
Patient education is a key management priority in patients with RP.
First-line treatment for RP is a calcium channel blocker; other agents that can be used include
angiotensin-II receptor antagonists and selective serotonin receptor antagonists. Phosphodiesterase type 5 inhibitors are increasingly being used to treat CTD-associated RP.
Digital ischaemic complications (ulcers and critical ischaemia) can occur in CTD-associated
RP, particularly in patients with SSc.
Intravenous prostanoid therapy should be considered in severe RP and digital ischaemic
complications.
Botulinum toxin injection and digital sympathectomy have been increasingly used in patients
with CTD-associated RP; however, further research is needed in this area.
Research agenda
To better understand the pathogenesis of RP, including transition to SRP, to drive therapeutic
advances.
To develop better outcome measures to facilitate future observational studies and clinical
trials.
To ascertain the clinical benefit of combination drug therapies.
To investigate existing drug therapies used in other conditions but without a strong evidence
base in CTD-associated RP, including (but not limited to) antiplatelet therapies/anticoagulants, statins and antioxidants.
To develop therapies directed towards novel therapeutic targets (e.g., inhibition of coldinduced sensitivity).
To better define the role of surgery in patients with RP (including ischaemic complications), in
particular, botulinum toxin injection and digital sympathectomy.
To develop locally acting therapies for RP, which are free of systemic adverse effects.
Disclosures
MH has nothing to disclose.
AH has undertaken consultancy work for Actelion and Apricus (Data Safety Monitoring Board). AH's
institution has received research grant funding from Actelion, and she has spoken at meetings sponsored by Actelion. AH has been a PI on a study sponsored by Orion (this study focussed on systemic
sclerosis-related Raynaud's phenomenon), and she is a PI on studies sponsored by Actelion (these
studies involve systemic sclerosis-related Raynaud's phenomenon).
129
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Best Practice & Research Clinical Rheumatology 30 (2016) 112e132

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Raynaud's phenomenon (RP) is a major cause of pain and disability

ischaemic digital complications (primarily ulcers and critical

Compressive (e.g., cervical rib) Obstructive: non-inammatory

Handearm vibration syndrome (vibration

number of different conditions including handearm vibration syndrome, extrinsic vascular

Calcium channel blockers

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