Fig. 6.1
Pallor phase in a patient with PRP
On examination there are no abnormalities. The skin of her fingers is cool but normal. Her upper limb peripheral pulses are easily felt.
Her general practitioner thinks that there is unlikely to be any significant cause of concern but arranges some further checks. Full blood count and erythrocyte sedimentation rate (ESR) are both normal and antinuclear antibody (ANA) testing negative. Nailfold capillaroscopy, performed at the local rheumatology department, is normal (Fig. 6.2).
Fig. 6.2
Normal nailfold capillaries (a) compared to abnormal dilated capillaries in a patient with SSc, with areas of avascularity (b)
A diagnosis of PRP is made. The patient is advised to speak to her employer and ask if she can change to working in warmer parts of the store: if this proves impossible then she is aware that it would be best to seek alternative part-time work. She is given a leaflet on RP, which gives information on keeping warm. Her doctor discusses starting nifedipine, but both he and the patient feel that this may not be necessary and the patient is concerned about the possibility of developing headaches, especially because this is her final year at university and she has a number of examinations coming up.
Definition
When RP is “primary” this means that it is idiopathic (of unknown cause). Importantly for the clinician, there is no underlying disease or condition to which it is secondary, and which might require specific treatment.
Allen and Brown in 1932 [4] discussed criteria for what was then termed “Raynaud’s disease”. More recent criteria proposed by LeRoy and Medsger in 1982 [5] (already discussed in Chap. 2) are summarised in Table 6.1, and are worthwhile considering in turn, because these highlight a number of key features relevant to the history, examination, and investigation plan:
Episodic attacks of acral pallor or cyanosis |
Strong and symmetric peripheral pulses |
No evidence of digital pitting, ulceration or gangrene |
Normal nailfold capillaries |
Negative antinuclear antibody (ANA) test (titre <1/100) |
Normal erythrocyte sedimentation rate (ESR) |
Episodic attacks of acral pallor or cyanosis: RP attacks are intermittent and resolve. This is usually true also for secondary RP, and so this criterion does not discriminate between PRP and secondary RP.
Strong and symmetric peripheral pulses: This helps to discriminate PRP from RP secondary to structural disease of large arteries, for example atherosclerosis or thromboangiitis obliterans (Buerger’s disease). However, this finding will not discriminate between PRP and RP secondary to SSc-spectrum disorders, nor to several other causes discussed in Chap. 10, when the problem lies primarily in the microcirculation and/or in intravascular factors (for example RP secondary to hyperviscosity syndromes).
No evidence of digital pitting (Fig. 6.3), ulceration or gangrene: This is a key point: by definition if a patient has progressed to irreversible tissue injury then this is not PRP and a secondary cause, for example SSc, must be looked for. It should be noted that (in contrast) the Allen and Brown criteria [4] included “gangrene or trophic changes limited in a large degree to the skin” and so could have included digital ulcers and scars which are now considered by most clinicians to be indicative of underlying disease.
Fig. 6.3
Digital pitting in a patient with SSc. Copyright Salford Royal NHS Foundation Trust
Normal nailfold capillaries: As discussed later, abnormal nailfold capillaries are predictive of a SSc-spectrum disorder.
Negative antinuclear ANA test (titre <1/100): A positive ANA is of concern, as this associates with connective tissue disease, especially when present in a high titre.
Normal ESR: Many secondary causes of RP, including connective tissue disease, malignancy and haematological disorders including diseases associated with hyperviscosity are associated with a raised ESR. A raised ESR demands an explanation.
It is worth mentioning that the criteria of LeRoy and Medsger [5] were a proposal: the diagnosis of PRP is not straightforward as discussed below under “transition”. An example of one of the challenges for clinicians is the definition of “normal nailfold capillaries”, as discussed in Chap. 12 and below under “investigation”.
Epidemiology
As already stated, PRP is very common. Women are more often affected than men. A detailed description of incidence and prevalence is given in Chap. 3. Community based studies which are questionnaire based usually do not include checking of all the parameters listed in Table 6.1 and will therefore most likely include some patients (for example) with abnormal nailfold capillaries or a positive ANA. However, pragmatically most individuals with RP who are not aware that they have an underlying causal disease/condition will have PRP.
Estimates of prevalence of PRP vary widely, as discussed in Chap. 3. To take two examples, a UK community study reported prevalences of RP of 19 % in patients attending surgeries and of 15 % in patients responding to a postal survey: attending surgeries, 21 % women and 16 % men affected; postal survey, 19 % women versus 11 % men affected [6]. A United States community-based study reported prevalences of 11 % in women and 8 % in men [7].
PRP typically presents in the teens or twenties. It is therefore especially important that a secondary cause is excluded when RP develops in older age groups. Children also may present with PRP [8]. The prevalence of RP in 12–15-year-olds has been estimated to be 15 % (18 % in girls, 12 % in boys) [9].
Pathogenesis
The pathogenesis of PRP is not fully understood, although in recent years there have been major advances in our understanding of the cellular and molecular basis of vasospasm, as discussed in Chaps. 4 and 5. The key point to make here is that the episodic imbalance between vasoconstriction and vasodilation which occurs in PRP is thought to be purely functional: structural vascular change does not occur. On this basis, abnormal nailfold capillaries exclude a diagnosis of PRP (Table 6.1). Although subtle abnormalities in nailfold capillaries have been reported in PRP [10] this may relate to the fact (discussed below) that the distinction between PRP and early SSc is not absolute.
The pathophysiology of RP is discussed in full in Chap. 5 and only a few points will be made here. When studying pathophysiology, investigators often compare patients with PRP to patients with SSc-related RP and to healthy controls: when abnormalities are found in patients with PRP, these may be less marked than in patients with SSc-related RP. Abnormalities in patients with PRP include reduced endothelium-dependent vasodilation [11–13], reduced expression in finger skin of the vasodilator calcitonin gene-related peptide [14], increased protein kinase activity and tyrosine phosphorylation [15], platelet activation [16–19], white blood cell activation [20] and oxidative stress [21]. Although some studies have suggested a role for endothelin-1 [22–24] the evidence (as discussed in Chap. 5) is conflicting. Genetic factors have also been implicated in the pathogenesis of PRP [25, 26], as discussed in Chap. 3.
History and Examination
The approach to diagnosis of the patient with suspected or definite RP is summarised in Fig. 6.4. The clinician must differentiate primary from secondary RP, and gauge the severity of the RP because this will inform treatment decisions.
Fig. 6.4
Flow chart summarising the approach to diagnosis of RP
In diagnosing and assessing severity of PRP, the key points in the history are:
1.
The typical colour changes of the fingers and toes (usually in response to cold exposure or emotional stress). Classically the fingers turn white (ischaemia), then blue (deoxygenation) then red (reperfusion), although many patients report only a uniphasic or biphasic response (including white or blue). The colour changes are confined to distal to the metacarpophalangeal joints, and can last variable lengths of time, but in patients with PRP usually resolve quickly (within minutes) after rewarming. Patients often report cold sensitivity rather than colour change of the feet which are less visible. The nose, ears and nipples [27] may also be affected (Fig. 6.5). Although attacks tend to be symmetrical, some fingers may be more affected than others. The thumbs are often spared, and if affected then this should prompt the clinician to be especially careful to exclude an underlying connective tissue disease [28]. It is worth highlighting that many people are cold sensitive, but for a diagnosis of RP, there must be colour change (Fig. 6.4).
Fig. 6.5
Cartoon of the “cold skin zones” in healthy control subjects (fingers, hands, toes, feet, knees, nose, ears): these are exaggerated in patients with PRP
2.
Absence of any symptoms suggestive of a connective tissue disease or of any of the other causes of secondary RP (Table 3.2). Therefore, it is essential to take a comprehensive history including a full systems enquiry (connective tissue disease can present with a wide range of symptoms, e.g. recent onset of heartburn could suggest oesophageal dysmotility), drug history, social history (with full occupational history including vibratory tool exposure, industrial chemical exposure) and family history (many patients with PRP have a family history of RP).
3.
Assessment of severity. Are the attacks painful and interfering with activities of everyday living?
On examination, the fingers and face should be carefully examined for sclerodactyly, digital pitting, digital ulcers, calcinosis, periungal erythema, telangiectases, and any capillary dilation or haemorrhages (at the nailbed) which are so marked as to be visible to the naked eye (Fig. 6.6). The peripheral pulses must be checked. A full examination is required for the same reason as a full history (e.g. basal crackles might indicate connective tissue disease-associated interstitial lung disease).
Fig. 6.6
Nailfold capillaries that were so dilated as to be visible to the naked eye (a) and as shown by capillaroscopy (b). This patient had dermatomyositis. Courtesy of H Chinoy. Copyright Salford Royal NHS Foundation Trust
Investigations
As directed by the criteria for PRP (Table 6.1), the basic set of investigations comprises a full blood count, ESR, ANA and nailfold capillaroscopy (Fig. 6.4). Many clinicians would also include a biochemical profile with thyroid function tests and (especially if symptoms are unilateral) a thoracic outlet radiograph to look for a cervical rib (Fig. 6.7). All should be normal in the patient with PRP.
Fig. 6.7
Bilateral cervical ribs
Many clinicians do not have access to nailfold videocapillaroscopy, which is the “gold standard” capillaroscopy technique (Chap. 12). A lower magnification technique should then be used: a stereomicroscope, dermatoscope [29, 30] or ophthalmoscope [31, 32]. There has been recent increased interest in the dermatoscope, which is a small portable hand-held piece of equipment which can be used in the office or outpatient clinic [33]. An advantage of lower magnification is that the whole nailbed is included in one field of view, although it is likely that more subtle abnormalities seen with high magnification videocapillaroscopy are missed. Figure 6.8 shows example images using the dermatoscope and videocapillaroscopy.
Fig. 6.8
Normal capillaries in a patient with PRP, imaged with a dermatoscope (top) and videomicroscope (bottom). The arrows indicate the position of the same capillaries using each technique. The higher magnification gives more detailed visualisation of the individual capillaries
It is worth highlighting that the interpretation of nailfold capillaroscopy images can be difficult. As discussed in Chap. 12, there is a wide range of “normality”: healthy controls do not all have evenly shaped “hairpin” loops (Fig. 6.2a) but can have considerable tortuosity of their capillaries. Figure 6.9 shows examples of capillary appearances which are not definitely “scleroderma-spectrum” but which nonetheless are not entirely normal. Also, it is not always possible to visualise everyone’s capillaries and this should not be mistaken for avascularity. However, definite abnormalities of a systemic sclerosis-spectrum disorder, for example giant capillaries, are not consistent with a diagnosis of PRP (Chap. 12).
Fig. 6.9
Nailfold capillaries in healthy control subjects showing (a) marked tortuosity (b) regular capillaries but with some variation in apical diameters. These images demonstrate the challenges in defining “normality”
Thermography, which measures surface temperature (Chap. 13), can help to differentiate primary from secondary RP, but is available only in certain specialist centres. Most thermography protocols will include a temperature challenge (Fig. 6.10), usually a cold challenge [34–36].
Fig. 6.10
Thermograms from a healthy control subject (upper), a patient with PRP (middle) and a patient with SSc (lower). The thermograms on the left are at 23 °C, and on the right at 30 °C. Although in both patients the fingertips are cold at 23 °C, this temperature gradient along the fingers normalises at 30 °C in the patient with PRP, but not in the patient with SSc (suggesting underlying structural vascular disease). The rewarming curves on the right show rapid rewarming in the healthy control subject, delayed (but complete) rewarming in the patient with PRP, and no rewarming within the 15 min observation period in the patient with SSc
A number of other methodologies which are used in research studies can help to distinguish between PRP and SSc-associated RP. These include laser Doppler flowmetry, laser Doppler imaging, finger systolic pressure measurement and plethysmography. They are discussed in Chap. 13.
Treatment
Many patients with PRP do not even seek medical advice, and most do not require drug treatment. Once the diagnosis of PRP is made, a key point is to reassure that patient that there is no evidence of any underlying condition, and that the aim of treatment is to minimise symptoms. Treatment of RP is discussed in detail in Chaps. 19 and 20, but some general points especially relevant to PRP will be made here.
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