Investigations into the pathogenesis of RP have been a long path lasting more than 150 years. Just two decades ago, Coffman wrote an editorial entitled “The enigma of primary Raynaud’s Disease” underlining the challenge of explaining digital vasospastic occlusion in the apparent absence of organic or structural causes [16]. The first contribution came from Claude Bernard’s studies in 1852 when he showed that the resection of the cervical sympathetic trunk in a rabbit is followed by a striking circulatory hyperreactivity on the side of the cut, together with increased warmth [17]. On this basis, Raynaud hypothesized that an “overactivity of the grey matter at the level of the spinal cord” was responsible for the distal vascular spasm and showed that the application of an ascending current through the spine was partially beneficial in treating his patients [1]. This observation provided the foundation for the “sympathetic theory” of RP. The first challenge to Raynaud’s hypothesis came in 1929 by Sir Thomas Lewis who observed that when reflex vasodilatation was induced through body warming, digital vasospasm could still be triggered by placing the hands in cold water (Fig. 1.2). Conversely, vasospasm could not be elicited by cooling the body when the hands were kept warm. He also showed that RP attacks could be induced in sympathetically denervated fingers and that vasospasm of the fifth digit could not be relieved by anesthetization of the ulnar nerve. This evidence led Lewis to conclude that RP was due to a “local fault” at the level of the digital arteries and not to a defect of the central nervous system [4, 5]. Thereafter, the study on RP pathophysiology focused mainly on these two theories: the Lewis’ “local fault” and the Raynaud’s “sympathetic theory.” In the late 1950s, Peacock showed that the hand blood flow can be restored by sympathetic blockade and that the digital blood collected from the dorsal vein of patients with primary RP had higher levels of catecholamines after cooling in comparison to healthy individuals [18, 19]. These data and the beneficial effects observed on RP symptoms after oral or intra-arterial reserpine, an inhibitor of synaptic catecholamine release, provided further support to Raynaud’s explanation [20–22]. Conversely, studies by Halpern (1960) and later Freedman (1989) showed that vasospastic attacks could be induced in denervated fingers substantiating Lewis’ observation [23, 24]. Jamieson hypothesized in 1971 that patients with RP likely have an increased “local” sensitivity to some aspect of the adrenergic transmission [25]. He showed that an ice cube applied for 10 s to the neck of an individual can reduce the distal digital blood flow and that this preconditioning was associated with more pronounced vasoconstriction in patients with primary or secondary RP (scleroderma) when their hands are immersed in cold water. This prompted him to conclude that the cold applied to the extremities sensitizes alpha-adrenoreceptor (αAR)-mediated mechanisms of vascular smooth muscle contraction, providing a view unifying the “local fault” with the “sympathetic” theories [25]. Further insight about the role of central versus peripheral sympathetic activity in RP was provided by studies conducted by Olsen and colleagues. They showed that a change in body posture from the supine to the sitting position (central reflex) can induce in primary patients with primary RP but not in healthy controls a drop of the digital blood flow and digital systolic pressure as a consequence of vasoconstriction and that this effect could be abolished by digital nerve blocking with lidocaine (peripheral reflex) [26]. The role of αARs was further explored in patients with primary RP using intra-arterial infusion of nonselective α₂-AR inhibitors (α_2A-, α_2B-, and α_2C-AR). This was followed by resolution of cold-induced vasospastic attacks, while α₁ blockade was ineffective [27]. Of note, the intra-arterial infusion of direct α₂-AR agonist did not induce significant vasospasm, failing to demonstrate a definitive role for this mechanism in RP [28–31]. The final entente between the sympathetic and the local fault theory was set in 2000 by Flavahan. He discovered that during cold exposure the normally “silent” α_2C-ARs relocate from the Golgi complex to the cell surface, driving a specific cold-induced vasoconstrictive response [15]. His studies confirmed that although the sympathetic stimulation is a major player driving vasoconstriction via the secretion of adrenergic agonists, a “local” sensitivity of the arterioles is crucial to mediate the exaggerated vascular response to cold in RP.

Raynaud’s disease had been initially reported as a rare disease. Sir William Osler described 19 cases out of 23,000 medical patients seen at the Johns Hopkins Hospital in Baltimore Maryland during a period of 20 years [32]. Monro analyzed the England and Scotland general hospital records reporting only 8 cases of diagnosed Raynaud’s disease among the 54,793 patients admitted in the decade after the translation of Raynaud’s thesis into English (1888–1897) [33]. Likely at that time RP was still largely underrecognized as well as underreported. Moreover, the lack of uniformed criteria to define RP represented another major problem. In fact, only later in 1932 Allen and Brown proposed the first set of criteria to define primary RP (they called it “Raynaud’s disease”) (see Diagnosis section). These criteria have been subsequently validated in a sample of 756 women diagnosed with RP at the Mayo Clinic between 1920 and 1945. Of the 629 cases with available complete information and long-term follow-up, 377 (60 %) met the criteria for primary RP, and in 95 % of the cases the “primary” diagnosis was confirmed, proving the utility of such criteria [34]. In the first survey conducted on a non-hospitalized population, 25 % of male medical students and 30 % of female nurses reported a positive history for “intermittent digital ischemia” (1933) [35]. The prevalence of RP in the general population has been subsequently estimated ranging from 1 to 19 % using postal and telephonic surveys in several worldwide geographic areas [36–45]. While for some of these studies a physician assessment of RP was required, a patient-reported history of cold-induced white or blue digital color changes sufficed for others. These surveys showed that RP is more prevalent in young women, younger age groups, and family members of patients with RP [36–45]. Interestingly, the advent of the worldwide web and the diffuse Internet use among the general population have dramatically increased the availability of medical information and boosted the ability to search information for a specific medical condition. “Raynaud’s phenomenon” (including all languages) is nowadays frequently queried through the most popular search engines. Intriguingly, data obtained from Google website shows a cyclical pattern for such searches, with a peak during winter months (January) every year (Fig. 1.3).

Historically, the diagnosis of RP has been eminently clinical, as suggested by Raynaud’s own words: “the phenomenon of dead finger was too well known by everybody for it to be necessary for me to delay in discussing it” [1]. He provided the first detailed description of the typical paroxysmal vasospasm to grant him the honor of the famous eponym. Emblematically, only 4 of the 25 patients described in Raynaud’s thesis would meet the definition of RP today, as he included several cases of thromboangiitis obliterans and atherosclerosis. In fact, during the following decades, an increasing number of publications began to use the term “Raynaud’s syndrome,” “Raynaud’s disease,” and “Raynaud’s phenomenon” to describe a heterogeneous group of clinical syndromes drifting away from the original Raynaud’s description. This brought Allen and Brown in 1932 to define the criteria for a clear and rigorous diagnosis of a primary disorder that could be appropriately called “Raynaud’s disease” [6, 7]. They collected 150 patients with suspected RP and carefully documented for each of them a complete neurologic exam, patency of the peripheral arteries, and available long-term follow-up. They concluded that the minimal requirements for diagnosis of primary RP were (1) intermittent attacks of discoloration of extremities excited by cold or emotions; (2) symmetric or bilateral distribution (Fig. 1.4); (3) presence of normal pulsation in the palpable arteries; (4) trophic changes, when present, limited to the skin and never consisting of gross gangrene; (5) absence of evidence of organic arterial occlusion such as cervical rib; and (6) symptoms of 2 years or of longer duration; secondary criteria included (1) female gender and (2) absence of pain [6, 7]. Allen and Brown’s criteria remained the main classification system for primary RP until 1992 when LeRoy and Medsger suggested introducing normal nailfold capillaries, negative test for antinuclear antibody, and normal erythrocyte sedimentation rate in addition to presence of symmetric attacks, absence of tissue necrosis, ulceration, or gangrene, and absence of obvious secondary causes (based on patient’s history and general physical examination) to discriminate between primary and secondary RP [8].

Several instrumental methods to diagnose and study RP have been developed over time, but only nailfold capillaroscopy has been consistently introduced in the clinical practice. Already in 1925 Brown and O’Leary were using nailfold capillaroscopic analysis to show evidence of microvascular abnormalities in RP secondary to systemic sclerosis (Fig. 1.5) [46]. Much later, the seminal work of Maricq and LeRoy in the 1970s gave the impetus for the capillaroscopy to become a major tool to study RP and to discriminate primary versus secondary disease. The use of this method allowed Maricq and LeRoy not only to meticulously describe specific nailfold capillary patterns in different connective tissue disorders, but also to observe specific functional variations. In fact, they noted that after cooling, the capillary blood flow is completely “standstill” in patients with scleroderma and “intermittent” in primary RP, while it remains “continuous” in healthy individuals [47, 48]. The technique to conduct the capillaroscopy was further developed under the impulse of several investigators up to the present time [49]. Other diagnostic tools such as videomicroscopy, thermography, angiography, and laser Doppler imaging have been used in the research setting and during clinical trials to obtain direct measurements of skin temperature and digital blood flow. However, none of them have as yet become part of the routine clinical assessment in RP patients [50, 51].

Since the early nineteenth century, the main approach to cold sensitivity (or RP) has been non-pharmacological and based on recommendations such as the use of warm clothing, improvement of lifestyle, and avoidance of excessive emotional distress [33, 52]. In 1945, Lipkin reported that “mental suggestion” improved RP manifestations in several patients, anticipating the research on the role of biofeedback (1973) and autogenic training (1978) [53–55]. “Swinging the arms counter-clockwise as fast as possible for few seconds” was suggested by others as a helpful practice for RP patients (1978) [56]. Several ancillary aids like electrically heated gloves and socks or chemical hand warmers have also been introduced to help people living in cold climates [57]. Importantly, most of these interventions failed to improve RP when tested in formal trials based on clinical outcomes such as hand temperature recovering time after immersion in cold water [58].

In the nineteenth century, several compounds had been tested for their proven or purported vasodilative effects including amyl nitrite, nitroglycerin, quinine, ergot, and thyroid extract; analgesics such as opium, phenacetin, or cannabis indica; and uricosurics like salicylic acid, sodium phosphate, and piperazidin. Also electricity has been reported as a potential treatment (galvanism and faradism). Typically, the whole body or the hands of the patients were placed in a warm bath and then electricity was directly applied to the water to suppress nerve conduction with the intent of improving circulation [33]. Partial benefit on RP symptoms has been attributed to the application of topical treatments such as oxygen baths, local bleeding, and “fomentations” with sedatives like belladonna or laudanum [33]. An interesting trial evaluating the vasoactive effects of ethylic alcohol has been conducted with some positive results. Vasko and Evans showed that ethanol (10 %) infused intravenously for 2 h (2 ml/kg/h) to eight patients with primary RP resulted in restored pulsatile digital blood flow in five of them [59]. The major challenge with this approach was that large amounts of whiskey, brandy, or other alcohol beverages had to be consumed (90–150 ml) in order to effectively relieve vasoconstriction, carrying considerable risk for intoxication. In fact, no other formal studies have been subsequently conducted using this approach.

Starting in 1862, RP therapy focused mainly on counteracting the sympathetic vasomotor regulation. Maurice Raynaud described beneficial treatments based on the application of ascending electrical current to the spinal cord of his patients with the purpose of achieving a noninvasive sympathetic block [1]. In 1902, Harvey Cushing introduced the use of the tourniquet technique. He noted that the release of a tourniquet from an extremity after limb surgery was inevitably followed by hyperemia associated with a higher than normal skin temperature. That forthcoming winter, this technique was applied for the first time to a young woman with a very painful vasospastic episode. A rubber band was applied tightly to the upper arm for about 2 min. After removal, a “bright flush of the extremity followed with increase of surface temperature and a much more readily palpable radial artery” occurred, in addition to temporary but effective relief of the pain [60]. He hypothesized that the pressure of the tourniquet could disrupt the sympathetic conduction along the artery, therefore interrupting partially the vasoconstrictive tone.

In 1889, cervical sympathectomy was introduced as a treatment for epilepsy. Such approach was unsuccessful and eventually abandoned. However, several patients reported hyperemia of the arms as a side effect of the surgery. These findings brought Adson to perform the first lumbar sympathectomy for RP in a teenage patient with a history of ulcers and painful vasospastic attacks to the feet. The second, third, and fourth lumbar ganglions were resected and the outer sheath of the common iliac arteries was stripped for a distance of about 5 cm. Following the operation, the feet turned warm and pink, with an increase of skin temperature [61, 62]. Since this successful episode, surgical sympathectomy became a widely used treatment for severe RP. Although the surgical technique improved over time, recurrence of symptoms and development of side effects such as ipsilateral paresthesia, Horner’s syndrome, or anhidrosis have been frequently reported [62, 63]. More recently localized microsurgical interventions have been developed to achieve a localized digital sympathectomy and more focal beneficial outcomes (1980) [64].

Alternative strategies to block sympathetic efferent impulses have also been pursued. A “chemical” sympathectomy has been introduced in practice using a direct local or intravenous sympathetic block (Bier block, 1974). In the first case, sympatholytic agents such as cocaine, reserpine, lidocaine, and bupivacaine were directly injected in the ganglia or in the proximity of affected districts (i.e., wrist or fingers) [65, 66]. In the Bier block, the veins of the involved extremity were emptied using an elastic bandage, and a blood pressure cuff was inflated to suprasystolic pressure to prevent reperfusion. A sympatholytic agent like guanethidine or reserpine (in 50–100 ml of normal saline) was then injected into a peripheral vein and left in place for 15–20 min before the arterial occlusion was slowly released. More recently, intradigital and palmar botulinum toxin A injections have shown some efficacy in restoring blood flow and achieving pain control [67–70].

The role of αAR was first explored in 1957 with an uncontrolled study on phenoxybenzamine, a nonselective inhibitor. A more refined pharmacological modulation of the sympathetic function was developed later in the 1970s with the use of reserpine and guanethidine. These molecules alter the sympathetic signal at the level of the synaptic terminal reducing the accumulation of norepinephrine and inhibiting the vasoconstricting action of nicotine and acetylcholine. Although in one study the use of reserpine in patients with RP showed an increase in digital capillary blood flow, no difference from placebo was observed in terms of number of vasospastic attacks and skin temperature [71, 72]. The direct inhibition of αARs by methyldopa (1969), prazosin (1979), indoramin (1986), and phentolamine (1987) subsequently emerged as an effective treatment in RP [73–76]. However, these drugs became obsolete due to nonselectivity and association with relevant side effects (i.e., orthostatic hypotension). More recently, after the discovery of the pivotal role played by alpha-2c receptors in mediating cold-induced vasospasm, novel specific αAR modulators are in the pipeline [77].

The direct vasodilator effect provided by nitroglycerin was exploited in RP through different formulations including sublingual drops (1899), tablets (1983), ointment (1948), tape (1994), and transdermal patches (1995). While beneficial, the use of nitrates has been limited by their short half-life and the frequent occurrence of systemic side effects [78–80].

The observation that RP is associated with the presence of other vasospastic disorders such as Prinzmetal’s angina and migraine suggested the possibility that a “diffuse vasospasm” is present in certain individuals [10, 81]. This prompted the introduction of nifedipine, a calcium channel blocker used for coronary vasospasm, as a more targeted therapeutic option to treat RP. The first successful trial with nifedipine was published in 1981 and was soon followed by two other double-blind, placebo-controlled, crossover studies in patients with primary and secondary RP [9–11]. These studies showed consistently a significant reduction of the frequency and the severity of RP attacks.