DÄ internationalArchive16/2021Raynaud’s Phenomenon: A Vascular Acrosyndrome That Requires Long-Term Care

Review article

Raynaud’s Phenomenon: A Vascular Acrosyndrome That Requires Long-Term Care

A vascular acrosyndrome that requires long-term care

Dtsch Arztebl Int 2021; 118: 273-80. DOI: 10.3238/arztebl.m2021.0023

Klein-Weigel, P; Sander, O; Reinhold, S; Nielitz, J; Steindl, J; Richter, J G

Background: Some 5–10% of the German population are affected by Raynaud’s phenomenon (RP). In around 10–20% of cases RP arises from an underlying disease, most commonly a connective tissue disease. This review encompasses the diagnosis and differential diagnosis of RP and examines the efficacy of the currently available pharmaceutical and non-pharmaceutical treatment options.

Methods: We conducted a selective literature search in PubMed using the search terms “Raynaud‘s phenomenon”, “Raynaud‘s syndrome,” “vasospasm,” “vascular acrosyndrome,” and “systemic sclerosis,” together with a search of the Cochrane Database of Systematic Reviews up to April 2020.

Results: Raynaud’s phenomenon mainly affects the fingers or toes and is typically triggered by cold or emotional stressors. The most important diagnostic steps are demonstration of a tendency towards digital vasospasm, exclusion of occlusions in the afferent arteries and acral vessels, nail-fold capillaroscopy, and determination of autoantibody status. Tumor screening should be arranged in the presence of B symptoms or first manifestation of RP in old age. The onset of RP in childhood is a rare occurrence and points to a secondary origin. The principal options for treatment are protection against cold and administration of calcium antagonists, which reduces the occurrence of RP by around 20–40 %. The treatment of RP in patients with systemic sclerosis is described in the recommendations of the European League Against Rheumatism (EULAR).

Conclusion: At onset or after years of latency, patients with Raynaud phenomenon may have an underlying disease (most commonly a connective tissue disease). Long-term specialist care is necessary for asymptomatic patients with risk factors and for those with clinically manifest symptoms of an underlying condition alike.

LNSLNS

Raynaud’s phenomenon (RP) describes an intermittent change in color in affected acra from white to bluish-cyanotic and finally to red, caused by vasospasm (ischemic phase) and subsequent vasodilation (hyperemic phase) of digital arteries (1) (Figure 1). It is not always the case that all three color changes occur. According to the European Society of Vascular Medicine (ESVM) guideline, a phase of white discoloration must, by definition, occur (1), while other authors also consider intermittent cyanosis to be sufficient (“blue Raynaud’s phenomenon”) (2). RP manifests primarily on the fingers and toes, and less frequently on other acra (1, 2). The duration of individual attacks varies, lasting on average 20 min (2). RP occurs at least once a day in 60% of patients, while 10% report between one and three attacks per month and 1% report occasional attacks (2).

Typical “white phase” of Raynaud’s phenomenon in the fingers
Figure 1
Typical “white phase” of Raynaud’s phenomenon in the fingers

Cold and emotional stressors act as triggers of the vasospasm (1, 2). It is extremely rare for RP to occur in the absence of these triggers. Since the color changes are regularly accompanied by pain, dysesthesia, motor impairment, and general cold intolerance, the term “Raynaud’s syndrome” is also commonly used in German-speaking countries. A distinction is made between primary Raynaud’s phenomenon (without underlying disease) and secondary Raynaud’s phenomenon (with underlying disease), with the most common being systemic sclerosis (1). The initial manifestation of RP can precede the onset of a connective tissue disease by years to decades (1, 2). The rate of transition from seemingly primary RP to secondary RP is approximately 10% over 10 years (3).

In addition to connective tissue diseases and vasculitis, other causal factors include arterial occlusion of other etiologies in the hand or arm, malignancies, hand arm vibration syndrome, and occupational exposure, for example to vinyl chloride (1). There is also an association with upper limb compression syndromes, the causality of which has not been elucidated (1). Raynaud’s phenomenon can also be triggered or exacerbated by medications and drugs (4) (Box). In primary FP, an increased incidence of affective and anxiety disorders has also been reported (5).

Medications/drugs that can trigger or exacerbate Raynaud’s phenomenon
Box
Medications/drugs that can trigger or exacerbate Raynaud’s phenomenon

The frequency of the presence of primary and secondary RP at the time of initial diagnosis varies depending on age (high probability of secondary RP in children and older patients). As a result of selection mechanisms in the referral process, greater familiarity with the differential diagnosis, and due to the fact that discriminatory testing methods such as capillaroscopy are virtually only available in specialized medical centers, secondary RP is diagnosed earlier and more frequently in such centers.

In the Framingham study, secondary RP was found in about 20% of cases, based on the general population (6). In a meta-analysis including 639 patients and a prospective study with 586 patients, 12.6 and 13.6%, respectively, of patients that first presented to a physician for RP developed a manifest connective tissue disease within 10–20 years (7, 8). Therefore, in the primary care setting, one can assume a low probability (10–20%) of secondary RP at the time of initial diagnosis.

Vasospastic syndrome describes the overlapping of RP with other disorders caused by vasospasm. Migraine is the most frequent concomitant disorder. Conversely, RP is found in every third to fifth migraine patient asked in a targeted manner (9), which is relevant in terms of differential therapy, since medications for the treatment and prevention of migraine can exacerbate RP (Box).

Prevalence in the population

The Framingham study found a prevalence of Raynaud’s phenomenon of 9.6% in women and 8.1% in men (6). For Germany, a prevalence of 5.8% has been calculated on the basis of more recent data (10). The frequency of RP depends on geographical latitude (being more frequent in the north than in the south) and altitude (being more frequent in mountainous regions than in lowland areas), and also varies according to season (occurring more often in the winter than in the summer) (1). Women tend to be more frequently affected compared to men, whereby the sex ratio varies in the literature (1, 2, 6).

Freedman et al. found a familial aggregation of RP in approximately 25% of first-degree relatives (11), while studies on twins demonstrated a higher heritability rate of 55% (12). A recent study identified an association with a variant in the NOS1 gene, the precise functional characterization of which is still awaited (13).

Pathophysiology

There are numerous reports of impaired temperature regulation and vascular responsiveness to cold stimuli in patients with primary Raynaud’s phenomenon. According to Flavahan, RP occurs primarily in skin areas with a high density of AV anastomoses, which are equipped with two different sympathetic transmission systems: norepinephrine (vasoconstrictive) and acetylcholine (vasodilatory) (14). Cold physiologically results in vasoconstriction of the AV shunts. Local cold exposure (hands, fingers) appears to be more important in this process than does the central sympathetic outflow, as induced by a drop in ambient temperature (14). In contrast to healthy individuals, patients with RP respond to local cold stimuli at finger temperatures of <25 °C with vasospasm, which advances to complete temporary vascular occlusion if the temperature is further reduced to an average of 19 °C (15). It is still largely unclear what role thermosensitive transient receptor potentials (TRPs) play in this process and how they interact with endothelial vasoactive peptides and neuronal effects (13). In systemic sclerosis, vasospasm encounters vessels that are already structurally compromised and stenosed by subintimal fibrosis, making it easier for RP to manifest (16).

Diagnostic approach

On the part of the primary care provider, it is important to take a detailed medical history, measure the patient’s pulse, and perform a functional test to evaluate blood flow to the hand via the radial and ulnar arteries (Allen’s test). The demonstration of a tendency towards digital vasospasm, the identification of brachial and acral artery stenosis or occlusion, the performance of nailfold capillaroscopy, as well as the determination of antinuclear antibodies (ANA) are specialist tasks primarily reserved for rheumatologists, angiologists, and dermatologists (17) (Table 1). If the patient exhibits B symptoms or new-onset RP in old age—the literature does not permit an exact cut-off value to be derived—tumor screening should also be initiated, since RP can also manifest as a paraneoplastic acrosyndrome in rare cases (18). There is no evidence of an association with specific malignancies (18). Differences between primary and secondary RP are listed in Table 2.

Workflow on the differential diagnostic investigation of Raynaud’s phenomenon
Table 1
Workflow on the differential diagnostic investigation of Raynaud’s phenomenon
Differentiation between primary and secondary Raynaud’s phenomenon (RP)
Table 2
Differentiation between primary and secondary Raynaud’s phenomenon (RP)

In the case of suspected occupational disease (for example, hand arm vibration syndrome), it is important to report this to the responsible employers’ liability insurance association in order to initiate an investigation procedure, and to seek the advice of a rheumatologist in the case of suspected connective tissue disease or vasculitis.

Looking out for “red flags” is crucial to the early detection of systemic sclerosis:

  • Raynaud’s phenomenon
  • Puffy fingers
  • Positive specific autoantibodies and/or
  • Abnormal capillaroscopy (8, 19). Advanced scleroderma-like disorders exhibit typical skin and hand changes, often accompanied by permanent acral ischemia (Figure 2).
Systemic sclerosis with permanent digital ischemia in hand/digital artery occlusion and early flexion contracture of the fingers
Figure 2
Systemic sclerosis with permanent digital ischemia in hand/digital artery occlusion and early flexion contracture of the fingers

Autoantibody determination

The determination of antinuclear antibodies (ANA) functions as a screening test for the presence or identification of an increased risk for the development of a connective tissue disease (1, 7, 8, 19). In a prospective study of 1039 patients, of which >10% were followed-up for more than 10 years, only 2% of patients with RP, no evidence of digital/hand artery occlusion, and negative ANA developed a connective tissue disease (20). However, the positive predictive value of ANA screening alone for the development of a connective tissue disease is low at approximately 30% (7). Therefore, in the case of a positive test, screening for extractable nuclear antigens (ENA) should always be additionally performed in order to detect specific disease-related antibodies (for example, anti-double-stranded DNA antibodies [anti-dsDNA ab] in lupus erythematosus [SLE], anti-topoisomerase antibodies in diffuse systemic sclerosis, anti-centromere antibodies in limited systemic sclerosis, and anti-Ro/SSA or anti-La/SSB antibodies in Sjögren’s syndrome) (21).

Nailfold capillaroscopy

This examination serves the same purpose as ANA screening (1, 7, 8, 19). At 47%, its positive predictive value is better than that of ANA screening (7). Capillaroscopy is able to clearly distinguish between “normal findings” and “abnormal findings” (interobserver agreement for “normal findings,” 0.95–0.98) (22). A nailfold capillary density of ≥ 7/mm, as well as hairpin-shaped and/or tortuous capillaries with a narrow apex speak strongly against the presence of a connective tissue disease (Figure 3). On the other hand, the practiced capillaroscopist is able to identify patterns of findings that permit their classification as a connective tissue disease with a high degree of probability and enable early detection of risk (interobserver agreement, 0.90–0.96) (22, 23). Apical ectasia, giant capillaries (apical diameter > 50 μm), as well as capillary loss and hemorrhage are the most readily reproducible morphological changes (24) (Figure 4).

Example of normal findings in nailfold capillaroscopy showing normal capillary density and normal capillary morphology
Figure 3
Example of normal findings in nailfold capillaroscopy showing normal capillary density and normal capillary morphology
Nailfold capillary morphological findings in systemic sclerosis
Figure 4
Nailfold capillary morphological findings in systemic sclerosis

Relevance of combining antibody determination and capillaroscopy

By combining specific autoantibody diagnostic tests and nailfold capillaroscopy, it is possible to identify significantly more at-risk patients compared to individual investigations (8). If, at the time of initial presentation due to Raynaud’s phenomenon, scleroderma-specific autoantibodies were positive and abnormal capillaroscopy showing capillary loss and capillary telangiectasia was also present, the adjusted hazard ratio for the development of a connective tissue disease within an observation period of up to 20 years was 60.08; 79.5% of the study patients developed systemic sclerosis. In contrast, isolated abnormal capillaroscopy or positive antibody detection alone were significantly less predictive, with adjusted hazard ratios of 5.03 and 8.5, respectively. If both investigations were normal, only 1.8% of patients developed systemic sclerosis (8). The present study supports the guideline recommendation to always perform both investigations at initial diagnosis of RP (1).

Specialist medical follow-up

There are no evidence-based recommendations to date on the duration or time intervals of follow-up. Due to limited angiology and rheumatology resources in Germany, specialist medical follow-up at 2- to 3-year intervals in clinically asymptomatic patients in whom specific autoantibodies have been detected and/or abnormal nailfold capillaroscopy has been recorded seems judicious to us. In our opinion, patients with a very high probability of primary RP (young women, positive family history, as well as no clinical, serological, or capillaroscopic abnormalities) do not require specialist follow-up. These patients should be advised to return for a specialist consultation if the RP worsens and/or hand/finger edema develops.

Raynaud’s diary

In order to better assess subjectively perceived impairment as well as the response to treatment, a Raynaud’s diary should be kept, at least temporarily (initial diagnosis, change of medication, phases of worsening), recording the frequency, duration, and severity of attacks (visual analog scale 1–10). A simplification and updating of data collection and transmission by means of a digital health application would be desirable in the future.

Treatment of Raynaud’s phenomenon

Drug treatment is not indicated in all cases of RP. In the case of infrequent attacks or mild subjective impairment, general measures to protect against cold, as well as avoidance of specific trigger situations, are sufficient (1). Table 3 summarizes the effects of non-pharmaceutical and pharmaceutical treatment interventions in RP.

Effects of non-pharmaceutical and pharmaceutical treatment of Raynaud’s phenomenon (RP)
Table 3
Effects of non-pharmaceutical and pharmaceutical treatment of Raynaud’s phenomenon (RP)

Non-pharmaceutical treatment

Protection from the cold, wet, and wind represents the overriding recommendation in terms of RP prevention (1). The scope of possibilities ranges from conventional gloves, heating pads, and pocket warmers to heated gloves, shoe inserts, and socks. To the best of our knowledge, the quantitative effects of these measures on the frequency of RP and quality of life of patients have not been investigated in a targeted manner as yet.

A controlled clinical study on the efficacy of low-level laser therapy showed favorable treatment effects in primary RP (25). RP was reduced on average by about one attack per day, while sham treatment only prevented one attack every 10 days. In addition, RP was somewhat less severe in the laser group. There were no differences in average outdoor temperature during treatment phases. The low number of cases limits the validity of these results. Data on quality of life were not recorded.

In a small controlled study of patients, a Spanish working group described positive effects for the use of galvanic current (20 sessions over 7 weeks), in addition to unspecified baseline pharmaceutical treatment, on the number and severity of RP attacks (26). The treatment effects were unusually pronounced, given that the frequency and intensity of RP in the control group consistently increased over the duration of the study. Since the outdoor temperature was not recorded as part of the study, these effects could be due to climatic differences. Data on quality of life were not recorded.

Relaxation exercises and biofeedback have been investigated primarily in smaller studies, which have been summarized in a meta-analysis (27). Due to a lack of control groups, it was not possible to quantify the treatment effects, meaning that no evidence-based recommendation could be made for or against these therapies (27).

In view of the disorders of emotionality and anxiety described in primary RP, psychotherapeutic treatment approaches are conceivable (5). To our knowledge, no interventional studies in this regard are available to date.

Pharmaceutical treatment

Drugs that induce vasospasm should generally be discontinued or switched (Box).

Dihydropyridine-type calcium antagonists are predominantly used to treat RP. A systematic Cochrane review showed an effect for calcium channel blockers primarily on the frequency of RP attacks (28). In untreated patients, an RP attack occurred approximately once per day. At best, calcium channel blockers reduced the frequency of attacks to around one every 2 days. Data on quality of life were not analyzed. Calcium channel blockers often cause adverse drug reactions that limit their use at the high doses tested (for example, 2–3 × 20 mg nifedipine) (hypotension, orthostasis, palpitations, peripheral edema, constipation).

The selective serotonin re-uptake inhibitor (SSRI) fluoxetine was tested versus nifedipine in a controlled study (29). The frequency and severity of RP was reduced. The extremely low number of cases limits the validity of these results. In addition, the publication suffers from severe formal deficiencies. Fluoxetine–like other SSRIs–can trigger vasospasm (30). It has the potential to cause central nervous and cardiac side effects, thereby making patient monitoring necessary. It is not officially approved in Germany for the treatment of RP.

Losartan reduced the frequency and severity of RP compared to nifedipine in a prospective randomized pilot study (31). The small number of cases limits the validity of these results. The observed increase in RP attacks under nifedipine is not explained. No outdoor temperature monitoring was carried out, meaning that temperature differences over the course of the study could have contributed to this increase. Data on quality of life were not recorded. Typical adverse drug reactions (ADRs) to losarten include hypotension, dizziness, fatigue, weakness, and headache. Losarten is not approved in Germany for the treatment of RP.

Controlled studies on the efficacy of phosphodiesterase-5 inhibitors (sildenafil, tadalafin, vardenafil) in primary RP have not been published. A meta-analysis of six randomized controlled trials in systemic sclerosis showed small to moderate positive effects on the frequency, duration, and severity of RP (32). At present, the European League Against Rheumatism (EULAR) makes a Grade A recommendation only for patients at high risk for digital ulcers and florid digital ulcers in the setting of systemic sclerosis (33). ADRs to phosphodiesterase-5 inhibitors include hypotension, cephalalgia, visual disturbances, myalgia, chest pain, dyspepsia, and nasal congestion. Simultaneous use of nitro-compounds must be avoided. PDE-5 inhibitors are not approved in Germany for the treatment of RP.

In a systematic Cochrane review, iloprost was able to reduce only the severity of RP (34). This effect is based on a single older study. Therefore, the authors conclude that it is difficult to find robust evidence for the effective treatment of RP with iloprost in systemic sclerosis (34). A 12-month treatment study with cyclical intravenous iloprost infusion resulted in an absolute risk reduction of 8% compared to nifedipine, albeit with disproportionately higher treatment complexity (35). For this reason, the EULAR recommends intravenous iloprost infusion only when oral treatment options have been exhausted or are not tolerated (33). Randomized clinical studies on the use of iloprost in primary Raynaud’s phenomenon have not been published. Common ADRs include headaches, flushing symptoms, hypotension, nausea, and vomiting.

Riociguat, a soluble guanylate cyclase stimulator, is considered to be a promising candidate for the treatment of RP, but is still in an early phase of clinical trials for this indication (36).

Botulinum toxins are potent neurotoxins produced by clostridia as exotoxins (BTX). In 2004, the first pilot study was published reporting the treatment of RP using perivascular BTX-A injections in the hand (37). BTX-B is now also used in this indication (38). Clinically, highly heterogeneous treatment effects were observed (38, 39, 40). Therefore, at present, the use of BTX cannot be recommended outside controlled clinical trials.

In summary, the efficacy of current drug treatment options for RP is limited and often only supported by low-level evidence.

Conflict of interest statement
Dr. Sander received speaker’s fees from Actelion.

The remaining authors declare that no conflict of interests exists.

Manuscript received on 26 June 2020, revised version accepted on 24 November 2020

Translated from the original German by Christine Rye.

Corresponding author
Dr. med. Peter Klein-Weigel
Klinik für Angiologie, Ernst von Bergmann Klinikum gGmbH
Charlottenstr. 72, 14467 Potsdam, Germany
p.klein-weigel@web.de

Cite this as:
Klein-Weigel P, Sander O, Reinhold S, Nielitz J, Steindl J, Richter JG: Raynaud‘s phenomenon—a vascular acrosyndrome that requires long-term care. Dtsch Arztebl Int 2021; 118: 273–80. DOI: 10.3238/arztebl.m2021.0023

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Department of Angiology, Klinikum Ernst von Bergmann, Potsdam: Dr. med Peter Klein-Weigel, Dr. med Simone Reinhold, Jessica Nielitz, Dr. med. Julia Steindl
Policlinic of Rheumatology and Hiller Research Unit Rheumatology, Düsseldorf University Hospital, Faculty of Medicinet, Heinrich Heine University Düsseldorf: Dr. med. Oliver Sander, Prof. Dr. med. Jutta G. Richter
Medications/drugs that can trigger or exacerbate Raynaud’s phenomenon
Box
Medications/drugs that can trigger or exacerbate Raynaud’s phenomenon
Typical “white phase” of Raynaud’s phenomenon in the fingers
Figure 1
Typical “white phase” of Raynaud’s phenomenon in the fingers
Systemic sclerosis with permanent digital ischemia in hand/digital artery occlusion and early flexion contracture of the fingers
Figure 2
Systemic sclerosis with permanent digital ischemia in hand/digital artery occlusion and early flexion contracture of the fingers
Example of normal findings in nailfold capillaroscopy showing normal capillary density and normal capillary morphology
Figure 3
Example of normal findings in nailfold capillaroscopy showing normal capillary density and normal capillary morphology
Nailfold capillary morphological findings in systemic sclerosis
Figure 4
Nailfold capillary morphological findings in systemic sclerosis
Workflow on the differential diagnostic investigation of Raynaud’s phenomenon
Table 1
Workflow on the differential diagnostic investigation of Raynaud’s phenomenon
Differentiation between primary and secondary Raynaud’s phenomenon (RP)
Table 2
Differentiation between primary and secondary Raynaud’s phenomenon (RP)
Effects of non-pharmaceutical and pharmaceutical treatment of Raynaud’s phenomenon (RP)
Table 3
Effects of non-pharmaceutical and pharmaceutical treatment of Raynaud’s phenomenon (RP)
1.Belch J, Carlizza A, Carpentier PH, et al.: ESVM guidelines – the diagnosis and management of Raynaud‘s phenomenon. Vasa 2017; 46: 413–23 CrossRef MEDLINE
2.Heidrich H, Helmis J, Fahrig C, et al.: Clinical characteristics of primary, secondary and suspected secondary Raynaud’s syndrome and diagnostic transition in the long-term follow-up. A retrospective study in 900 patients. VASA 2008; 37: S2–25 CrossRef
3.Hirschl M, Hirschl K, Lenz M, et al.: Transition from primary Raynaud‘s phenomenon to secondary Raynaud‘s phenomenon identified by diagnosis of an associated disease: results of ten years of prospective surveillance. Arthritis Rheum 2006; 54: 1974–81 CrossRef MEDLINE
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