Raynaud’s Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment

Abstract

Raynaud’s phenomenon (RP) is a condition characterized by episodic, excessive vasoconstriction in the fingers and toes, triggered by cold or stress. This leads to a distinctive sequence of color changes in the digits. Pallor indicates reduced blood flow due to oxygen deprivation, while erythema appears as reperfusion. RP can be primary, with no identifiable underlying cause, or secondary, associated with other conditions. These conditions include autoimmune diseases, most commonly systemic sclerosis, vascular diseases; and neurological conditions. While the exact cause of RP remains unclear, genetic and hormonal (estrogen) factors are likely contributors. The pathogenesis of RP involves a complex interaction between the vascular wall, nerves, hormones, and humoral factors, disrupting the balance between vasoconstriction and vasodilation. In primary RP, the vascular abnormalities are primarily functional. However, in secondary RP, both functional and structural components occur in blood vessels. This explains why digital tissue damage frequently occurs in secondary RP but not primary RP. Diagnosis of RP is primarily clinical. Recent advancements in imaging techniques have aided in diagnosis and monitoring, but nail fold capillaroscopy remains the gold standard for distinguishing between primary and secondary RP. If there are signs of acute ischemic injury, vascular imaging, particularly preoperatively, is crucial to rule out other vaso-occlusive conditions. Management of RP focuses on alleviating symptoms and preventing tissue damage. Vasodilator medications are the first-line treatment when general measures like warmth and stress management are not sufficient. Dihydropyridine calcium channel blockers (CCBs), such as nifedipine, are commonly used for vasodilation. Phosphodiesterase-5 inhibitors and prostaglandin analogs are alternative options for patients who do not respond to CCBs or have ischemic tissue damage. Bosentan, an endothelin-1 receptor antagonist, has shown effectiveness in treating and preventing digital ulcers, especially in patients with multiple ulcers. For severe cases, botulinum toxin injections or sympathectomy surgery can be used to control RP symptoms. However, botulinum toxin injections require repeated administration, and sympathectomy’s long-term effectiveness is uncertain. Fat grafting is a promising surgical therapy for promoting healing and preventing tissue injury.

INTRODUCTION

Raynaud’s phenomenon (RP) is an episodic excessive vasoconstriction that typically occurs in response to cold exposure or stressful conditions and manifests as characteristic color changes in the digits [1-3]. Originally described as a disease by Maurice Raynaud, RP was later reclassified as a “phenomenon” by Hutchison due to its association with various underlying conditions, rather than a single disease entity [2,4]. Vascular spasms predominantly affect the digits, although other sites such as the tip of the nose, ears, and nipples may also be involved [3].

RP is broadly classified into primary and secondary. Primary RP is an idiopathic condition without a discernible underlying cause, whereas secondary RP is associated with other conditions. These include autoimmune rheumatologic diseases, of which systemic sclerosis (SSc) is the most common, and non-rheumatologic conditions such as vaso-occlusive diseases (e.g., Buerger’s disease) and neurologic, hematologic, malignant, and occupational conditions [5-13]. Therefore, although rheumatologists primarily diagnose and manage RP, particularly in association with SSc, a multidisciplinary approach is often required.

Primary RP is more common in females than in males, although males tend to experience a higher incidence of the disease early in life. Reported prevalence varies widely across studies (2.1%-22.4%) due to factors like geographic location, ethnicity, and differing definitions used [3,12,14]. While the exact cause of RP remains unknown, genetics plays a role [15]. Hartmann et al. [15] conducted a genome-wide association study (GWAS) and identified gene loci potentially involved in the pathogenesis of RP. They also discovered druggable genes that hold promise for drug repurposing in the management of RP. Further research is required to validate these findings. Although estrogen levels and smoking may contribute to RP, these risk factors are inconsistent and require further investigation [12,16].

Furthermore, there is much to understand about RP’s significant advancements in our understanding since it was first described. Therefore, based on the current updates available on the pathogenesis, diagnostic workup, and treatment of RP, including refractory cases, this review aims to provide a comprehensive general overview of RP.

PATHOPHYSIOLOGY OF RP

The complex pathogenesis of RP remains incompletely understood [11,17]. A review by Herrick [11] categorized contributing factors as “vascular, neural, and intravascular”, highlighting the intricate interplay between these aspects. Recent research has also implicated neurohumoral factors and signaling pathways like Rho-associated protein kinase (RhoA/ROCK) and reactive oxygen species (ROS) [17,18], which hold promise as potential treatment targets.

Primary and secondary RP likely follow distinct pathogenetic pathways [11,19,20]. In primary RP, vascular abnormalities are primarily functional, while secondary RP exhibits both structural and functional impairments [11,17]. To understand RP pathogenesis, it is essential to explore the two main categories of cutaneous microcirculation: cutaneous capillaries, responsible for nutrient supply, and arteriovenous anastomoses (AVA), which play a role in thermoregulation [21].

Primary RP originates from a functional abnormality of thermoregulatory AVAs. This leads to exaggerated vasospasm after cold exposure, while the structurally intact nutritional capillaries prevent tissue ischemia, explaining the absence of such damage in primary RP [17,21]. In contrast, secondary RP is characterized by structural abnormalities in the nutritional capillaries, leading to frequent tissue ischemia and thermoregulatory dysfunction [11,21]. Notably, the abundance of AVAs in hairless glabrous skin areas might explain why digits are particularly susceptible to RP attacks [11,21].

Endothelial dysfunction, a key factor in secondary RP, particularly SSc, disrupts the endothelium’s normal function [21]. The endothelium produces angiotensin II and endothelin-1, potent vasoconstrictors with profibrotic and proliferative properties [21]. While some evidence suggests impaired endothelium-dependent vasodilation and elevated endothelin-1 levels in primary RP as well, these findings remain inconclusive [12,22]. Furthermore, studies showed that vascular smooth muscle cells (VSMCs) and the adventitia play important role in the pathogenesis of RP [11,19,21].

The “neural” pathogenic mechanism may originate from cold-induced increased sympathetic tone or, in some cases, peripheral nerve compression. Increased sympathetic activity triggers the release of neurotransmitters, which interact with specific receptors on VSMCs, leading to vasospasms [11,21]. Thoracic outlet syndrome (TOS) may cause RP symptoms due to irritation of the sympathetic nerves around the subclavian artery [23].

Regarding “intravascular” factors, both primary and secondary RP involve platelet activation and the subsequent release of vasoactive substances like thromboxane and serotonin, which further promote platelet aggregation [11,24]. While fibrinolysis is impaired in SSc and other connective tissue diseases (CTD)-associated RP, it remains normal in primary RP [11,25]. Impaired erythrocyte flexibility and increased blood viscosity in RP contribute to the rationale for using rheologic drugs like pentoxifylline to improve blood flow [26]. Additionally, hematological conditions that elevate plasma viscosity, such as cryoglobulinemia, paraproteinemia, cryofibrinogenemia, and paraneoplastic disorders, can lead to digital hypoperfusion and present as RP [13]. A summary of the factors involved in RP pathogenesis is presented in Fig. 1.

Fig. 1.

Pathogenesis of RP. Vascular changes can be classified as functional, in primary RP, and both functional and structural, in secondary RP. The pathogenesis of RP involves an interplay of the vascular, intravascular, and neuronal factors (non-mutually exclusive) and cold- or stress-induced signaling pathways. Endothelial dysfunction contributes mainly to the pathogenesis of systemic sclerosis. Vascular smooth muscle hypertrophy is implicated in conditions such as hand-arm vibration syndrome; increased blood viscosity in hematologic conditions and impaired erythrocyte flexibility may induce manifestations of RP. Increased sympathetic tone with neurotransmitter release or peripheral nerve compressions in conditions, such as the thoracic outlet or carpal tunnel syndrome, contributes to RP pathogenesis. RP, Raynaud’s phenomenon; VSM, vascular smooth muscle; RBC, red blood cell; ROS, reactive oxygen species; RhoA/ROCK, Rho-associated protein kinase; NT, neurotransmitters; VSMC, vascular smooth muscle cells; TOS, thoracic outlet syndrome; CTS, carpal tunnel syndrome.

CLINICAL MANIFESTATION

Raynaud’s phenomenon manifests as reversible, symmetrical, and sharply demarcated skin color changes primarily affecting the digits, but also occasionally involving the nose, earlobes, and nipples [6,27]. Typically, a sequential 3-phase color change occurs, with pallor followed by cyanosis and then erythema. These phases represent ischemia, deoxygenation, and reperfusion, respectively, although some cases may only exhibit a 2-phase change (pallor and cyanosis) [2,6]. Patients may also experience numbness or burning pain.

Primary RP typically has an onset between 15 and 30 years of age, with no evidence of tissue injury, normal nailfold capillaroscopy (NFC) findings, negative autoantibody tests, and no signs of potential underlying conditions [2]. Notably, the thumb is generally spared, likely due to its anatomical and vascular supply peculiarity. However, some studies suggested that thumb-sparing could also be a manifestation of secondary RP [28].

In contrast, secondary RP can lead to frequent digital tissue damage and ulceration due to underlying structural abnormalities in blood vessels. Chronic secondary RP may even cause irreversible color changes in the digits [11,21]. Furthermore, secondary RP may co-occur with clinical manifestations of underlying autoimmune rheumatologic diseases, such as photosensitivity, skin rashes, oral ulcers, hair loss, ocular and oral dryness, and muscle weakness [3,6]. In some cases, RP may even serve as an early warning sign before a diagnosis of autoimmune disease, with patients gradually developing these symptoms over time [20].

When RP is associated with neurological conditions like carpal tunnel syndrome (CTS), patients typically experience numbness and tingling along the median nerve distribution, with nocturnal worsening of pain. Treating CTS may also improve RP symptoms [29]. Similarly, TOS can cause pain and paresthesia in the arm or hand [23].

Vaso-occlusive conditions, such as thromboembolism or atherosclerosis, should be considered in the differential diagnosis of RP. However, these conditions typically present asymmetrically with pulse differences. Imaging is crucial to exclude them [3,27,30].

Buerger’s disease, an inflammatory vascular disease primarily affecting young male smokers, can manifest with RP symptoms and share some management strategies like vasodilation. However, due to the involvement of distal vessels, surgical revascularization is less effective in Buerger’s disease compared to endovascular therapies [10].

Other conditions that mimic RP include acrocyanosis and erythromelalgia. Acrocyanosis presents with persistent, symmetrical, bluish discoloration of the digits triggered by cold and often accompanied by local sweating. Unlike RP, it lacks paroxysmal pallor attacks [31]. Erythromelalgia, on the other hand, manifests as intermittent redness of the hands or feet resembling RP erythema. It may be associated with underlying myeloproliferative conditions like polycythemia vera. A key distinction is that cold exposure alleviates symptoms of erythromelalgia [32]. Table 1 summarizes the key differences between clinical and laboratory findings of primary and secondary RP.

Table 1.

Comparison of clinical manifestations of primary and secondary Raynaud's phenomenon

Characteristic	Primary RP	Secondary RP
Sex	Female>Male	Varies based on the cause (e.g. SSc: female>male; Buerger’s disease: male>female)
Age at onset	Young (age: 15-30 y)	Beyond 40 y of age
Genetics	30%-50% of first-degree relatives	Less common
Status of microcirculation	Structurally intact, with functional disturbance	Both structurally and functionally impaired
Thumb sparing	More common	May occur
Pain or paresthesia	Rarely occurs	Frequently occurs, and may be severe
Ulcers or trophic changes	Absent	Usual (sclerodactyly, telangiectasia, etc.)
Course	Reversibility of the ischemia is a rule	Tissue injury (ulceration), ischemia, and tissue necrosis may occur
Accessible vascular pulses	Symmetrically normal pulse	Depending on the etiology, it could be normal, weak, absent, and/or asymmetric
Laboratory data	ANA: negative or low titer ESR: normal	ANA: often positive ESR: often elevated
NFC	Appears normal	Abnormal capillary structures

RP, Raynaud’s phenomenon; NFC, nail fold capillaroscopy; SSc, systemic sclerosis; ANA, antinuclear antibody; ESR, erythrocyte sedimentation rate.

DIAGNOSIS

1) History and physical examination

Raynaud’s phenomenon is a clinically diagnosed condition with heterogeneous causes. Due to its heterogeneity, a comprehensive evaluation to rule out potential underlying causes is crucial [3,8,33-35]. Differentiating primary from secondary RP is essential as they have distinct severities, treatment approaches, and prognoses [6,36].

Clinical history and physical examination are the cornerstones of diagnosis. Patient-provided photographs documenting vasospastic episodes can further support the clinical picture [37]. While some laboratory tests and imaging studies may aid in distinguishing primary and secondary RP [5,38-40], strategies like cold provocation to induce vasospastic attacks are not recommended [41].

The clinical history should delve into the patient’s sex, age at onset, patterns of digital involvement (including thumb sparing, symmetricity, and ulcerations), and frequency of RP attacks [2,42]. Additionally, it is crucial to identify potential secondary causes of RP, such as SSc, other autoimmune diseases, hematologic disorders, paraneoplastic conditions, and neurological or vaso-occlusive conditions (as discussed in the clinical manifestation section) [5,20,43]. Occupational risk factors like exposure to manual vibrating tools, chemicals (e.g., polyvinyl chloride), medications (e.g., β-blockers and chemotherapy), and smoking history should also be explored [23,29,44].

Focused physical examinations should include comprehensive skin and musculoskeletal evaluations. This includes checking for puffy hands with indurated skin, sclerodactyly, digital ulcers, and pitting scars, which may suggest SSc. Fixed contractures might also be present (Fig. 2) [20,45]. Mucosal ulcers, muscle weakness, joint swelling, and tenderness should be documented. Proximal macrovascular evaluation involves assessing accessible vessels through bilateral pulse palpation and blood pressure measurements in both arms. This helps identify potential external compressive conditions or systemic vascular diseases [20,23]. Some of the characteristic skin and musculoskeletal changes in SSc are shown in Fig. 2.

Fig. 2.

Changes in the hands of patients with progressive SSc. (A) Swelling of fingers (puffy hand) is noticed in the early edematous phase of SSc. (B) Induration of the skin and loss of skin folds over the fingers, with deformity of the distal tuft of the right index finger. (C) Fixed contracture secondary to constrictive indurated skin is demonstrated in a patient in an advanced phase of SSc. (D) X-ray image of the hand in the stage shown in (B). Digital pulp atrophy with acrolysis (arrowheads) and calcinosis cutis (arrow) are observed. (E) Digital ulcers (arrows) may develop because of poor blood flow related to SSc vasculopathy. SSc, systemic sclerosis.

2) Laboratory investigation

Laboratory investigations may include complete blood count, C-reactive protein level, and erythrocyte sedimentation rate (ESR). Depending on the clinical picture, additional tests like antinuclear antibodies (ANA), extractable nuclear antibodies, thyroid function tests, and serum plasma electrophoresis might be performed [6,20]. In suspected cases of compressive lesions, such as TOS, radiography can be used to identify cervical ribs [23]. Radiographs may also reveal digital acroosteolysis and calcinotic cutis in patients with SSc (Fig. 2) [46].

Generally, a diagnosis of primary RP requires fulfilling specific criteria, including no underlying CTDs, normal physical examination findings, a normal NFC test, a negative or low-titer ESR, and an ANA titer ≤1:40 [33].

Several diagnostic criteria for RP exist, with some minor variations. All criteria share the core principle of requiring cold-induced digital skin color changes [33,37,47]. Earlier criteria by Maricq and Weinrich [37] and Brennan et al. [47] categorized RP diagnosis as a spectrum of possibilities: “negative”, “possible”, and “definite”. The absence of cold-induced color changes falls under “negative”, effectively ruling out RP. More recently, Maverakis et al. [33] proposed alternative criteria, establishing entry criteria for heightened digital sensitivity to cold and a color change with at least 2 phases (pallor and cyanosis). If these criteria are met, they recommend proceeding with a scoring system based on seven additional components. Table 2 compares this newer criterion with one of the earlier diagnostic criteria.

Table 2.

Comparison between one of the older Raynaud’s phenomenon diagnostic criteria and the recently reported one

Maverakis et al. [33]	Brennan et al. [47]
Biphasic color change of at least pallor and cyanosis is a required entry criterion.	Uniphasic digital color change (pallor, cyanosis, or erythema) is considered a “possible” RP case.
For a definite RP, a “three-step” approach is used as follows: 1) The patient should be positive for both of the following screening questions: ①Heightened cold sensitivity of the digits. ②Two-phase (pallor and cyanosis) skin color changes. 2) Then fulfill ≥3/7 of the following criteria. ①Inciting factors other than cold, such as stress ②Both hands were affected although not simultaneously and/or non-symmetric ③Accompanying sensory symptoms such as paresthesia and/or numbness ④Distinction of the color changes is distinctive between the affected and unaffected skin. ⑤Provided photographs of RP episodes by the patient do support the diagnosis. ⑥Involvement of other body sites such as nose, ears, feet, and areola ⑦Three-phase color change during vasospasm (white, blue, red).	A “definite” diagnosis of RP is made by episodes of biphasic color change (at least two of the pallor, cyanosis, and erythema) in either a cold or normal environment.
No description of severity is included	Repetitive attacks of RP with paresthesia and numbness in the cold or normal environment were described as severe RP.

RP: Raynaud’s phenomenon.

3) Imaging modality

Drawing on insights from previous reviews, we can categorize imaging techniques used for RP diagnosis into two groups: those assessing microvasculature structural integrity and those examining vascular function by directly or indirectly measuring blood flow in the digits.

① NFC

Normal nailfold capillaroscopy is a crucial imaging tool that provides detailed information about the structural condition of capillaries in the nail folds [48]. The capillaries at this site lie horizontally in a plane similar to the skin, making it the preferred location for imaging [2,5]. In settings with limited resources where videocapillaroscopes are unavailable, alternative options include less expensive and more portable devices like ophthalmoscopes or dermatoscopes. However, interpreting results obtained with dermatoscopy requires caution due to its lower sensitivity compared to videocapilloroscopes [5].

Before performing NFC, certain preparatory measures are commended. These include avoiding coffee, smoking, and vasoconstrictive medications for 4-6 hours before the test, and allowing the patient to acclimatize to room temperature for 15-30 minutes. Digits with mechanical injuries and thumbs are generally excluded from the NFC evaluation [49]. In cases where examining fingernail folds is difficult, toenail folds can be an alternative, although the results may be influenced by less severe RP in the toes [42,50]. While time-consuming, evaluating all eight fingers provides better sensitivity compared to examining the ring finger [49].

Although a normal NFC finding typically suggests primary RP [33,51], distinguishing between normal and abnormal images, and further classifying abnormal patterns as “scleroderma” or “non-scleroderma”, can be challenging [33]. This complexity arises from variations in capillary morphology, even among healthy individuals, and the lack of clear pathological significance for some isolated abnormal findings [52]. A detailed discussion of NFC patterns is beyond the scope of this review. However, comprehensive qualitative, semi-quantitative, and quantitative capillary measurements are recommended.

NFC findings of enlarged capillaries (diameter >50 µm) and decreased capillary density (evidenced by dropouts, or less than 7-10 capillaries per millimeter in the distal capillary row) are crucial indicators of scleroderma-spectrum disorders [5,49,52,53]. Additional studies suggest that enlarged capillaries, along with hemorrhages, might indicate early and active SSc, while capillary disorganization with a bushy appearance and dropouts may be linked to late-stage disease [53,54]. A 20-year prospective study even identified capillary loss and enlargement as independent predictors of progression to definite SSc [55]. The various patterns observed in NFC are illustrated in Fig. 3.

Fig. 3.

Patterns observed using nail fold capillaroscopy. (A) NFC. (B) Normal NFC patterns in patients with primary Raynaud’s phenomenon. (C-E) NFC patterns in patients with progressive SSc indicate the effects of tissue hypoxia. (C) Early patterns include the presence of megacapillaries (black arrowheads) and microhemorrhages (black arrows). (D) Active patterns show an increased number of megacapillaries (black arrowheads) and microhemorrhages (black arrows). (E) Late patterns include neoangiogenesis with bushy capillaries (white arrowheads) and loss of capillaries (white arrows), with avascular areas. NFC, nailfold capillaroscope; SSc, systemic sclerosis.

② Perfusion scintigraphy (Raynaud’s scan)

Perfusion scintigraphy is a functional imaging technique that directly assesses blood flow in the digits using a tracer radioactive substance, such as Technetium-99m pertechnetate. Different protocols exist, with or without cooling the fingers. However, the one-hand-chilling method is often preferred [56,57]. Regardless of the protocol, perfusion scintigraphy has proven effective in distinguishing between normal and RP, as well as between primary and secondary RP [56,57]. Dynamic blood flow studies measure finger-to-palm ratios, helping differentiate healthy individuals from those with RP. Static blood pool phase studies, on the other hand, aid in discriminating between primary and secondary RP [41,56]. Fig. 4 illustrates perfusion scintigraphy findings in healthy individuals compared to those with RP.

Fig. 4.

Findings of perfusion scintigraphy (Raynaud’s Scan). In perfusion scintigraphy, dynamic blood flow and blood pool images are obtained and used for the discrimination of patients with RP from normal individuals. Perfusion scintigraphy may be done with or without cold stimulation. The one-hand chilling method is widely used for cold stimulation, wherein the non-dominant hand or the hand with more severe symptoms is dipped in cold water (4°C) and the ratio of the finger blood-pool count of the chilled hand to that of the ambient hand (normal>0.8) is calculated [56]. (A) Negative result of perfusion scintigraphy: the ratio of the finger blood-pool count of the chilled hand to that of the ambient hand was 0.98. (B) Positive result of perfusion scintigraphy: the ratio of the finger blood-pool count of the chilled hand to that of the ambient hand was 0.65. RP, Raynaud’s phenomenon.

③ Thermography

Thermography is an indirect method for evaluating digital blood flow by measuring temperature changes during skin rewarming after cold exposure [58,59]. An infrared camera captures the emitted infrared radiation from the skin, which reflects its temperature. Portable mobile phone thermography offers a convenient alternative [59]. O’Reilly et al. [60] observed that following cold exposure (15°C water for 1 minute), patients with primary RP exhibited slower, partial temperature recovery compared to healthy individuals. In contrast, patients with SSc showed no rewarming phase at 15 minutes. Similar to perfusion scintigraphy, thermography lacks standardization, limiting its standalone use [58,59]. However, combining thermography with other imaging modalities may improve diagnostic sensitivity [58].

④ Laser Doppler imaging

Laser Doppler imaging (LDI) utilizes the principle of the Doppler effect. Light emitted from circulating red blood cells induces a color change that correlates with the blood flow velocity [58]. LDI can help differentiate primary RP from SSc-related RP, and its findings correlate with those of thermography and NFC [61].

⑤ Other structural vascular imaging

For patients with acute limb ischemia, computed tomography angiography and magnetic resonance angiography can be valuable tools to exclude other occlusive causes, particularly before surgical intervention [62]. These techniques provide detailed images of blood vessel anatomy. Dynamic Doppler sonography is a non-invasive imaging modality that aids in differentiating primary from secondary RP. It also facilitates the measurement of various parameters, including vascular diameter (distal radial and ulnar arteries), blood flow volume, and post-cold provocation blood flow normalization [63].

MANAGEMENT

Despite advancements in understanding the pathogenesis of RP and its management, a curative treatment remains elusive. Additionally, the lack of validated treatment outcome measures has posed a challenge in conducting randomized controlled trials (RCT). However, the development of outcome-measuring scores, such as Raynaud’s Condition Score, has facilitated progress in several RCTs [64]. Furthermore, advancements in imaging technologies have led to a greater focus on using laser Doppler or thermography for objective outcome measurement of treatment responses [65].

The core principles of RP management focus on symptom relief, improved quality of life, and preventing potential tissue damage. These principles can be categorized into general measures, pharmacotherapies (further subdivided into first-line, add-on options, those for severe refractory RP with acute ischemic injury, and those with uncertain benefits), surgical therapies, other therapies, and additional therapies (Table 3).

Table 3.

Management of Raynaud’s phenomenon.

	Treatment	Indication	Pros	Cons	Remark
General measures	Keep the whole body warm, anxiety and stress management, stop smoking, avoid microtrauma (vibrating manual machines), avoid vasoconstricting drugs (nasal decongestants [pseudoephedrine], amphetamines, ergotamine)	All patients with RP	Easily accessible to every patient	-	All patients should be encouraged to practice general measures
Pharmaco-therapies	CCBs: nifedipine (30-120 mg/d), amlodipine (5-20 mg/d)	Uncomplicated RPs that do not respond adequately to general measures	Availability (affordability)	Headache, hypotension, and edema	Extended-release dihydropyridine CCBs are preferable Nondihydropyridine CCBs are generally avoided due to inconsistent effect
	ARBs (losartan 50 mg/d); topical nitrates; SSRIs (fluoxetine 20 mg/d); pentoxifylline (400-mg/BID or TID)	Uncomplicated RPs that do not respond adequately to CCBs alone or cannot tolerate CCBs	Useful if CCB escalation is limited by the side effects SSRIs: may be helpful to RP with anxiety disorder	-	Use of an ARB for other indications (eg, hypertension, heart failure, proteinuric chronic kidney disease)
	Endothelin-1 receptor antagonists (bosentan start at a dose of 62.5 mg/BID); prostaglandin analogs (IV-iloprost 0.5-2.0 ng/kg per min over 6 h daily/5 d); PDE-5 inhibitors (sildenafil 20 mg/TID, tadalafil 10 mg on alternate d and escalate based on the response); short-term anticoagulant	In cases of acute ischemic injury Short-term anticoagulant: severe RP at risk of associated arterial thrombosis for 1 to 2 days to minimize propagation of any possible thrombus	Digital ulcer-healing (bosentan, sildenafil, IV-iloprost) and preventing effect (bosentan, tadalafil)	Bosentan: hepatotoxicity and teratogenicity Iloprost infusion: headaches, flushing, nausea, jaw pain, and hypotension	Long-term IV-iloprost may have a disease-modifying effect in patients with SSc Sildenafil use in digital ulcer prevention needs further study
	Low-dose anti-platelet, long-term anti-coagulant, statins	Anticoagulation for those with a risk of vascular thrombosis	-	-	The benefit of antiplatelet therapy with aspirin is overall uncertain No evidence for the use of anticoagulation therapy for RP alone
Surgical therapies	Sympathectomy (Proximal cervicothoracic, thoracic, or lumbar sympathectomy; Digital sympathectomy, periarterial sympathectomy)	Failed optimal medical therapy/ before irreversible deep tissue damage	-	Proximal sympathectomy: rarely, Horner syndrome, pneumothorax Digital sympathectomy: digital amputation and recurrent ulceration	Technique standardization is needed Uncertain long-term effectiveness
	Fat graft	Failed medical therapy	Accelerates ulcer healing	Rarely, cellulitis at the fat harvest donor site	Standardization is needed
Other therapies	Botulinum toxin A (intradigital and palmar botulinum toxin A)	Patients with severe RP who are not responding to or tolerating vasodilator therapy As a trial prior to surgical intervention	-	Transient weakness of intrinsic muscles of the hand	Dose standardization is needed Repeated injections may be needed
Additional therapies	Antibiotics	If bacterial superinfection is likely	Control infections	-	-
	Debridement or wound care	As indicated	May help in wound healing	-	-

RP, Raynaud’s phenomenon; CCBs, Calcium channel blockers; ARB, angiotensin II receptor blockers; SSRI, selective serotonin reuptake inhibitors; PDE-5, phosphodiesterase-5; IV, Intravenous; QD, once daily; BID, twice daily; TID, three daily; –, not available.

1) General measures

Patient education regarding lifestyle modifications is the cornerstone of managing both primary and secondary RP. This includes advice on avoiding cold exposure; warming the entire body, not just hands and feet, by dressing in layers and covering the head [2,66]; smoking cessation; stress and anxiety management; avoiding medications with vasoconstrictive effects; and avoiding microtrauma from excessive vibrations [45,67].

2) Pharmacotherapies

When general measures prove insufficient, medications are considered. Drug selection depends on several factors, including whether there is prolonged irreversible ischemia or ulceration, drug availability, and cost. Medications used for RP management can be broadly categorized as vasodilators, inhibitors of vasoconstriction, or modulators of endothelial function [67, 68].

① First-line pharmacotherapy

(1) Calcium channel blockers

Calcium channel blockers (CCB) are the first-line vasodilator medications used for RP management. They work by inhibiting calcium influx into the smooth muscles of blood vessel walls, thereby ameliorating vasospasm [69]. Dihydropyridine CCBs are preferred because they primarily affect peripheral circulation rather than the heart, unlike non-dihydropyridines [70]. Additionally, extended-release formulations of nifedipine (10-40 mg twice daily) or amlodipine (5-10 mg daily) are favored over immediate-release options. This is because extended-release types cause a smaller increase in sympathetic activity, which can have side effects [71].

A meta-analysis of seven RCTs found that they minimally reduced the frequency and severity of RP attacks, but not the duration [72]. However, a larger meta-analysis of 38 RCTs showed CCBs decreased attack duration, frequency, and severity. They were also more effective in patients with primary RP compared to secondary RP [70].

The role of CCBs in healing digital ulcers remains unclear. A recent study suggests that they may be less effective in preventing or healing these ulcers [73]. High doses of CCBs can cause side effects like headaches, hypotension, and edema. Therefore, starting with a low dose and gradually increasing it is recommended [70].

(2) Add-on therapies

For patients who do not respond well to CCBs, alternative medications can be considered. These include topical nitrates, selective serotonin reuptake inhibitors (e.g., fluoxetine 20 mg per day), and angiotensin II receptor antagonists (e.g., losartan 50 mg per day). Unlike angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists may be beneficial for RP [2].

Another option is pentoxifylline, a vasoactive methylxanthine that promotes vasodilation by inhibiting cyclic adenosine monophosphate phosphodiesterase, increases blood flow by decreasing blood viscosity, promoting erythrocyte flexibility, and inhibiting platelet adhesion. Pentoxifylline is well-tolerated at a dose of 400 mg, and taken 2 to 3 times daily [26].

② Pharmacotherapy for severe refractory RP (with acute ischemic tissue injury)

(1) Endothelin-1 receptor antagonists

Endothelin-1 receptor antagonists work by blocking endothelin receptors. Bosentan, a dual endothelin-1 receptor inhibitor, has been studied for its potential role in treating digital ulcers in patients with SSc. Two double-blind, placebo-controlled trials showed that bosentan reduced the risk of new ulcer formation in SSc patients, especially those with multiple existing ulcers, but failed to demonstrate ulcer-healing effect [74,75]. However, these trials were short-term, making it difficult to definitively assess bosentan’s effectiveness in healing ulcers [74-76].

In contrast, some open-label retrospective studies suggest bosentan may not only prevent new ulcers but also promote healing, with a starting dose of 62.5 mg twice daily and a gradual increase to 125 mg twice daily [77,78]. A 3-year prospective study supports this, demonstrating positive results for ulcer healing in SSc patients treated with bosentan [78]. Another uncontrolled trial suggested that early administration of bosentan might improve its healing efficacy in SSc and mixed connective tissue disease patients with digital ulcers [77].

It is important to note that bosentan has no short effectiveness in reducing RP symptoms (frequency, severity, and duration) in SSc patients without digital ulcers [79]. Based on its positive effects on ulcers, the Korean Food and Drug Administration approved bosentan for treating digital ulcers in SSc patients. However, due to potential side effects like liver damage and birth defects, regular liver function monitoring and pregnancy testing are crucial for women of childbearing age during bosentan treatment [80].

(2) Phosphodiesterase-5 inhibitors

The treatment of patients with RP and critical ischemia of the digits should always prioritize ruling out other vaso-occlusive conditions that may necessitate interventional procedures (refer to the Diagnosis section for more details). Phosphodiesterase-5 (PDE-5) inhibitors, such as sildenafil (starting dose: 20 mg three times per day) and tadalafil (10 mg on alternate days), are used as second-line therapies after failed CCB therapy [80,81].

PDE-5 inhibitors work by blocking PDE-5, an enzyme that degrades cyclic guanosine monophosphate (cGMP). cGMP is a crucial molecule involved in nitric oxide (NO)-induced vasodilation [82]. These medications can be used as add-on therapy or an alternative for patients who do not respond well to CCBs.

The placebo-controlled Sildenafil Effect on Digital Ulcer Healing in sClerodErma study demonstrated the effectiveness of sildenafil (20 mg three times daily for 12 weeks) in healing digital ulcers. While sildenafil monotherapy did not significantly improve healing time, combination therapy with sildenafil and bosentan accelerated the process [83]. Case reports also support their concurrent use [84]. Additionally, a double-blind randomized crossover study showed that daily tadalafil 20 mg treatment for 6 weeks prevented new ulcer formation in patients already receiving first-line vasodilators [85]. However further investigation is needed to confirm the “prophylactic” benefits of sildenafil on digital ulcers [80].

(3) Prostaglandin analogs

Patients with evidence of acute ischemic injury to the digits and ulcers would benefit from prostanoids, preferably intravenous (IV) iloprost [80]. Prostaglandins act not only as vasodilators but also have fibrinolytic and platelet-aggregation-inhibiting properties. Studies from the early 1990s confirmed the effectiveness of short-term treatment with the prostacyclin analog IV iloprost (0.5 - 2.0 ng/kg per minutes over 6 hours daily for 5 days) in accelerating digital ulcer healing in patients with SSc [86,87]. While IV iloprost is generally well-tolerated, it can cause infusion-related rate effects like headaches, flushing, and nausea [87]. Moreover, recent studies suggest that long-term IV cyclic iloprost treatment may have disease-modifying effects [68,88,89]. However, data regarding whether IV iloprost prevents ulceration is inconclusive [90].

Oral iloprost has yielded mixed results. Some studies have not shown significant benefits for digital ulcer healing, while others report lower efficacy compared to parenteral iloprost [80]. Beraprost, an oral prostanoid, has shown promise in some uncontrolled studies, but a double-blind study found no significant difference compared to a placebo [91]. The use of inhaled prostaglandins for treating RP remains unclear.

③ Pharmacotherapies of weak evidence

There is limited evidence and no strong recommendation for the use of antiplatelet agents or long-term anticoagulation therapy in RP management. However, short-term low-molecular-weight heparin (LMWH) anticoagulation may be used in specific cases of acute limb ischemia. A single placebo-controlled study by Denton et al. [92] involving 30 patients showed that LMWH reduced the severity of RP symptoms, but this finding has not been replicated in other studies.

Statins exert vasoprotective effects through anti-apoptotic protection of the endothelium [6], inhibit the RhoA/ROCK pathway, increase NO production, and reduce endothelin-1 release. Statins are effective in SSc and decrease the severity of RP attacks [2,6]. Considering the role of Rho-kinase in RP pathogenesis, Rho-kinase inhibition may theoretically be effective for RP management. However, a double-blind, placebo-controlled, randomized trial by Fava et al. [93] showed no significant effect of fasudil, a Rho-kinase inhibitor.

Through a GWAS, Hartmann et al. [15] identified 211 drug-targeting genes proposed to be involved in the pathogenesis of RP, ADRA2A, and IRXA. This, in turn, has prompted further research on drug repurposing. Although clinical trials for RP are challenging, early-phase laboratory studies that include a broader range of the identified drugs could offer better guidance for the development of targeted therapies for RP. Additionally, there is growing interest in further studies on topical treatments, which may help mitigate the issue of drug discontinuation due to the side effects of systemic medications.

2) Surgical therapy

① Sympathectomy

Sympathectomy is a surgical option for patients with persistent tissue ischemia despite optimal medical therapy. It aims to relieve vasospasm by interrupting sympathetic nerve signals to the digital arteries [94]. There are two main surgical approaches: proximal (cervical) sympathectomy and local digital sympathectomy. Proximal sympathectomy is performed in the upper chest and is no longer the preferred treatment due to a higher rate of recurrence of RP symptoms after the procedure [7]. Local digital sympathectomy involves severing sympathetic nerves supplying the palmar digital arteries in the hand through a palmar incision [95,96].

The long-term effectiveness of both local and proximal sympathectomies for RP is unclear. A systematic review suggested that thoracoscopic sympathectomy might offer long-term benefits in secondary RP, but the effect in primary RP may only last up to 6 months [97]. Pace and Merritt [94] reported some long-term benefits with an “extended” (peri-ulnar) periarterial sympathectomy technique, but another study found no lasting effects, although it did note short-term improvements [98].

Potential complications of proximal sympathectomy include Horner syndrome, rebound hyperhidrosis, and pneumothorax [97,98]. Furthermore, most studies on sympathectomy for RP have been retrospective, and the surgical techniques have lacked standardization. Prospective studies are needed to establish more definitive evidence and to standardize the procedure for better outcomes.

② Fat graft

Fat grafting is a surgical option for patients with RP who do not respond to medical therapy and require surgical intervention. It has shown promise in improving symptoms and accelerating the healing of digital ulcers. This therapy is believed to work by promoting neovascularization through the action of stem cells present in the grafted fat tissue [99]. Fat grafting is generally well-tolerated, with a rare complication of cellulitis at the fat harvest site [99]. However, further research and standardization of this technique are needed [7].

3) Other therapies

① Botulinum toxin

The established mechanism of action of botulinum toxin A involves blocking the release of acetylcholine [18]. However, how botulinum toxin works in RP is not entirely clear. One proposed mechanism suggests it disrupts the production of ROS in VSMCs, which might then decrease the activity of α2C-adrenoreceptors and actin-myosin, ultimately leading to relaxation. Botulinum toxin may also improve chronic pain by affecting the signaling of substances like substance P and glutamate [18].

The results of past studies on botulinum toxin for RP are mixed due to variations in the patient groups studied. While some studies have not shown a clear improvement in blood flow, others report benefits for both symptoms and blood flow with botulinum toxin injections [100]. This treatment is generally well-tolerated, with the main side effect being a temporary weakness in the small muscles of the hand [100].

However, there are some drawbacks. Botox injections need to be repeated periodically, and some patients may develop resistance to the treatment. Additionally, there is no standardized dosage for botulinum toxin use in RP [18].

② Additional care

Pain control is crucial in managing RP with acute limb ischemia. Local debridement and wound care are performed when necessary to remove dead tissue to promote healing. Antibiotics are prescribed if there is a possibility of bacterial infections [45].

CONCLUSION

A better understanding of RP pathogenesis compared to its initial description has spurred advancements in therapeutic strategies. Imaging technologies now play a crucial role not only in aiding diagnosis but also in facilitating the monitoring of treatment responses. Nevertheless, gaps persist in our knowledge of RP, encompassing its etiology, the most effective treatment modalities, and standardized methods for assessing treatment response. Broadly, the management approach for RP involves general measures and pharmacotherapy as the first line of treatment, with surgical intervention reserved for severe, non-responsive cases. However, standardization for diagnosis and the surgical procedures performed for treatment. Therefore, further efforts are required to improve our understanding of RP and refine treatment approaches to optimize patient outcomes.