Diagnosis—The diagnosis of secondary RP is dependent on a comprehensive history, careful physical examination and specific laboratory investigations. These features are discussed in general terms below and in more specific detail in relation to the individual associated conditions later in the chapter.

History of RP depends on first confirming that there is indeed a clear history of episodic vascular insufficiency affecting the extremities that is triggered by specific factors such as cold exposure, emotional stress, exercise and on occasion an aggravating medication. An important consideration is the age and gender of the patient. Secondary RP more often occurs in older individuals. It is much more likely when there is no clear history of RP or cold sensitivity prior to the age of 30. In particular it is important to carefully assess whether RP symptoms might in fact have been present for longer than first suggested by the patient who may ignore mild symptoms for many years. Associated symptoms may reflect an underlying connective tissue disease. The presence dermatitis, dry eyes or mouth (sicca symptoms), finger swelling, muscle weakness, fatigue and arthralgia or arthritis are especially important. Symptoms of upper gastrointestinal dysmotility such as dysphagia or heart burn in a patient with RP may indicate a secondary connective tissue disease like SSc. These symptoms of gastrointestinal reflux disease are an important sensitive indicator of disease but very non-specific as these symptoms are very prevalent in the general population that often become more severe or prominent in middle age; the same time that a CTD might be suspected. Finger swelling or puffiness can be the first sign of a CTD and warrants detailed investigation and serial observations. It is, however, not uncommon to have this in primary RP when it likely reflects transient increase in digital vascular permeability. The need to have rings enlarged is an important but again non-specific feature that may suggest an underlying CTD. A history of digital infarction or ulceration or other major trophic change or skin does not occur in primary RP. In addition digital nail abnormalities such as nail dystrophy or onycholysis should be sought, although nail changes are also common in primary RP [4].

On examination it is important to elicit any signs of CTD including those of SLE, SSc or dermatomyositis. There are some specific signs that may point to an associated vasculitis—such as purpura or skin infarcts. Ordering a laboratory test to detect a haematological disorder such as cold agglutinin disease or cryoglobulinaemia is appropriate in cases with typical skin lesions. These are discussed in more details below. It is especially important to identify any internal organ complications as it may be that these develop early and before a defined diagnosis is made. This is evidenced by the relatively high frequency of RP in clinics assessing lung fibrosis, chronic liver disease or pulmonary hypertension as these may all occur in the context of mild CTD in which RP is an important clue to the presence of an associated autoimmune or inflammatory disease. When confronted with an organ based disease and RP, it is important to do further investigations to make a specific diagnosis, as it will not only define therapy for the associated disease by also the approach to management of RP. One of the most important investigations to highlight likelihood of secondary RP are nail fold capillaroscopy defined microvascular structural abnormalities [5, 6] [see Chap. 12]. There are specific patterns seen in particular with SSc and other CTDs including SLE, idiopathic inflammatory myopathies (IIM) that can help in diagnosis. Cases of undifferentiated CTD are typically associated with altered nail fold capillaries. The presence of enlarged and giant capillaries with haemorrhages for example suggests early morphological evidence of altered microcirculation in SSc (see Chap. 12). The typical SSc-NVC patterns occur in minority (2–15 %) of patients with SLE particularly those with RP, anticardiolipin antibodies and anti-U1RNP antibodies [7–9]; these cases likely to represent a cohort of patients with subclinical overlap syndrome. A greater variety of capillary abnormalities on the other hand are described for SLE. The most common NVC in SLE are capillary tortuosities with enlargement (2–88 %) but these changes may also occur in other connective tissue diseases [10–12]. The SSc-specific NVC pattern with microhaemorrhages and giant capillaries is on the other hand common among patients with IMM in particular dermatomyositis, and less so in polymyositis [13]. In contrast, there is a growing support that normal capillaroscopy should be incorporated into the diagnostic requirements for RP but it is noteworthy that there is a wide range of nailfold patterns seen in healthy individuals. Other forms of vascular imaging can be used to confirm the presence of RP—such as infrared thermography or laser Doppler flowmetry [14, 15] [see Chap. 13].

Autoantibody testing [see Chap. 15] is also central to the investigation of patients with a suspected diagnosis of secondary RP. In cases with a CTD, the serology testing will usually show a positive ANA pattern. The ANA may be secondary to an uncharacterized auto antigen or it may define a specific reactivity such as anti-centromere staining. It is sensible to test any patient with significant RP symptoms as part of baseline investigation and subsequently if there are any new clinical features suggesting the development of an associated connective tissue disease. A negative ANA or low titre ANA (e.g. 1:40 by indirect immunofluorescence) on the other hand would support the diagnosis of primary RP. In the context of secondary RP, there may be disease-specific ANA reactivities that help with diagnosis. Indeed, specific autoantibodies are associated with disease and now are included in the classification criteria for SLE, SSc and IIM [1, 16]. The prognostic significance of altered nail fold capillaroscopy findings and a positive ANA reactivity in patients with isolated RP is discussed in more detail elsewhere (see Chaps. 12 and 15). It should be remembered that some of these cases will fulfil criteria for very early diagnosis of systemic sclerosis (VEDOSS).

In addition, changes in biomechanical properties of the proximal vascular arterial system have been evaluated in distinguishing secondary from primary RP [17]. For example, increased carotid stiffness and elasticity or reduced carotid compliance as determined by ultrasound measurement using a Doppler scanner was found among SSc patients but not among those with primary RP [17]. Interestingly, this difference in vascular stiffness between SSc and primary RP was not observed for muscular femoral arteries.

Risk stratification—refers to the specific features that are present in a patient at diagnosis or early in the clinical course that predict specific progression, likelihood of progression or risk of developing a specific complication of the disease. The concept of risk stratification is borrowed from other medical fields but has particular resonance to the investigation and management of cases with suspected secondary RP.

The most robust markers of progression in a case of true isolated RP are the presence of abnormal nail fold capillary pattern and positive ANA. The specific pattern of ANA is important because a disease-associated antibody is more predictive of an underlying autoimmune disease. For example, a nucleolar pattern of ANA is more likely to be associated with progression from RP alone to definite SSc. It has been determined in a number of large series that the risk of developing CTD is around 15 % within 5 years of the onset of RP. The risk increases with length of follow-up and is much higher if a specific disease related ANA reactivity is present [9, 18]. Making a precise diagnosis of a CTD diagnosis is challenging as this is often a reflection of experience, expertise and clinical suspicion and the interpretation of the presence of a number of clinical features. It is complex in that many features such as skin changes or symptoms of gastrointestinal reflux disease (GERD) in themselves are not specific. Of more importance is the negative predictive value of normal capillaroscopy and negative ANA. It is very rare to develop a defined CTD if these tests are negative on two occasions separated by a minimum of 12 months of follow-up. The most robust evidence for this concept is the long term follow-up reported in a series published by Koenig et al., a prospective study that is congruent with earlier individual series and a meta-analysis [19, 20].

Thermography characteristics of secondary RP have now been evaluated and may eventually provide additional information for risk stratification. This approach together with other non-invasive methods of assessing vascular reactivity to cold challenges may help define a secondary process causing RP [see Chap. 13]. The sensitivity and specificity of these features is currently under investigation and will be important together with other practical considerations in introducing this into routine clinical practice.