While the onset of primary RP can be at any age, it is three times more common in those aged less than 40 years by which time in one prospective study of 424 people with RP, 73 % had developed symptoms [13]. Many patients with RP who are less than 40 years of age have a family history of primary RP [14]. RP appearing after the age of 40 years is considered late onset. In these patients, a positive family history is less common and secondary RP is more likely than primary [13]. Only 3 % of cases develop after the age of 60 [13].

The prevalence of primary RP is consistently higher in women compared with men, being up to four times more common [15, 16]. This is particularly true for people aged less than 40 years as women are more likely to develop RP at a younger age and the prevalence of RP increases with age in men, as occupational exposures and atherosclerotic disease become more prevalent [17]. Prevalence rates of RP in men only exceed those in women in the setting of occupational exposure to vibration and hand trauma (Chap. 9).

Risk profiles differ between men and women. Fraenkel et al. reported that twice as many women who had been widowed, divorced or separated had RP than those who were married or had never married, suggesting emotional stress may have a role, but this relationship was not observed in men [17]. They also found that alcohol use doubled the risk of developing RP in women but not in men, while smoking increased the risk of RP in men only (odds ratio [OR] 2.6, 95 % CI 1.1–6.3) [17]. In contrast, another study found no association with either alcohol or smoking [18]. In both sexes, a lower body mass index is associated with a higher risk of developing RP, perhaps due to greater sensitivity to cold temperatures [15]. Whether the increased prevalence of RP in women is related to hormonal factors is unknown [17].

Relatively few environmental risk factors have been identified and many studies are cross-sectional or do not control for other factors.

In addition to triggering attacks, colder climate may have an aetiologic role. Subjects who have ever lived in colder climates have a higher prevalence of primary RP [19]. Few studies have directly compared the prevalence in different climates [19, 20] but the prevalence is generally higher in cooler locations, with Maricq et al. reporting rates up to 20.2 % in women and 12.7 % in men in cool mountainous regions [19].

The association with occupational factors such as vibration injury in particular, is well known but occupational risks have not been examined in most population studies of primary RP. Exposure to solvents, for example in medical laboratories, is associated with a higher prevalence of RP with symptoms of RP occurring more commonly in the absence of cold [21].

Up to 50 % of subjects with primary RP have a family history of RP in first-degree relatives, particularly in women and in those with early onset RP [22, 23]. This suggests a genetic susceptibility although shared environmental factors could also contribute. In a study of female twins in the UK, Cherkas et al. found the concordance rates for cold sensitivity, RP and severe RP were all higher among monozygotic than dizygotic twins with heritability of 53 %, 55 % and 53 % respectively. Moreover, a potential contribution from the shared environment for all three traits was rejected [24].

Frech et al. found the relative risk of RP in first-degree relatives of patients with SSc compared with first-degree relatives of controls was 6.38 (95 % CI: 3.4–11.8) with decreasing risk with more distant relationships [25] This was greater than the risk of having SSc (RR 3.07) or an autoimmune disease (RR 2.49) and suggests the vasculopathy of RP is a heritable condition related to the vasculopathy of SSc but large genetic studies in this area are lacking. Polymorphisms of various candidate vasoactive mediator genes were not associated with RP in a small study of 95 cases [23]. Genetic abnormalities in the expression of type I interferon that predispose to abnormal endothelial cell senescence and apoptosis have been linked to SSc vasculopathy [26]. Similarly, a type I interferon signature on gene expression profiling may be associated with RP. This occurs in the setting of biallelic loss of protein expression mutations in the gene for tartrate-resistant acid phosphatase associated with bone dysplasia and increased autoimmunity including RP [27]. A two stage microsatellite-based genome wide study of six multi-case families in 2000 identified the β subunit of the muscle acetylcholine receptor and the serotonin 1B and 1E receptors as possible candidate genes for RP susceptibility [27]. For many common diseases, single-nucleotide polymorphism-based, genome-wide association studies have been performed to identify genetic risk variants with great success. Despite the supportive evidence for a genetic component to the development of RP, such an approach has not yet been utilised. This is perhaps due to the lack of a sufficiently large collection of suitable cases with DNA available, and/or to the cost of such a study.

Polymorphisms in clotting factors leading to increased microvascular thrombosis do not appear to be increased in patients with primary RP [28].

Genetic factors may also influence the predisposition to secondary RP related to environmental factors such as vinyl chloride monomer (VCM) induced RP. A case-control study of 58 subjects with RP from a population of 305 French workers with a history of VCM exposure, found no association between M1 and GST T1 genetic polymorphisms of glutathione S-transferases, involved in VCM metabolism, and RP when analysed separately but when combined, were significantly associated with RP when compared with other combinations of genotypes (OR = 2.1, 95 % CI = 1.1–3.8) [29]

Secondary RP occurs less frequently in the general population than primary RP, with a variable prevalence that depends on the underlying disorder (Table 3.2). Only 10 % have a positive family history [36].

In a small study of 118 patients seen in a rheumatology clinic in Italy, patients were classified as primary RP (29.7 %), secondary RP (53.3 %) or a third group with features suggestive of an underlying autoimmune disease but who did not yet meet full diagnostic criteria (16.9 %) [37]. An autoimmune disease was the most common underlying diagnosis in the secondary RP group (42.3 %), with SSc being the most common (25.4 %) followed by RA (7.6 %), SLE (5.9 %) and Sjogren’s syndrome (1.7 %). Other major causes included vibrating tools and atherosclerosis (both 2.5 %) [37].

Similarly, a multicentre study in Italy of 761 patients with RP found primary RP in 35.2 % and secondary RP in 64.8 % of patients. SSc was the most common autoimmune disease (28.4 %) followed by SLE (6.8 %) and RA (5 %) [38]. A large proportion of patients (82.5 %) classified as having primary RP had isolated features consistent with potential future development of an autoimmune disease. Common features included arthralgia (56 %), painless swelling of fingers (23.9 %), dryness of the mouth (21.6 %), migraine headaches (20.5 %), dryness of the eyes (16.8 %) and arthritis (15.7 %). This highlights the limitations of classifying RP into purely primary and secondary subtypes [38].

The annual incidence of secondary RP in the general population is unknown but among 112 patients with RP (73 % with primary RP, 14.3 % with secondary RP and the remainder suspected RP) attending a rheumatology clinic, followed for 5 years, the annual incidence of a concomitant disease that indicated secondary RP was 1.4 % [39].