Nailfold Capillaroscopy

Fig. 12.1

(a, b) The nailfold videocapillaroscope. The morphology of the nailfold dermal papillary capillaries is being studied by first putting a drop of oil on the nailfold and afterwards putting the device (lens) on the nailfold. The capillaries can be immediately visualised on the screen of the computer

How to Perform Capillaroscopy

Techniques: The Wide-Field, High-Magnification and the (Semi)-automated Technique

Capillaroscopy may be performed with a lens with low and high magnification. The instruments with low magnification (e.g. stereomicroscope [magnification ×14], dermatoscope, ophthalmoscope) allow a global evaluation of the entire nailfold area (wide-field capillaroscopy) [17]. These instruments allow a panoramic vision of the whole nailfold microvascular network. In this way, prompt localisation of abnormalities and analysis of architectural characteristics are performed (pattern recognition or qualitative assessment). The videocapillaroscope not only allows low magnification but also has the advantage of sequential high magnifications (magnifications ×100, ×200, ×600) which enable detailed observations of separate capillaries. When using the videocapillaroscope with a magnification of ×200, four consecutive images of 1 mm per nailfold are often taken, in order to view representative sections of the whole nailfold. Next to the wide-field and the high-magnification technique the semi-automated nailfold videocapillaroscopy (NVC) has emerged recently. This technique combines the advantages of the two previous techniques: concomitant high magnification combined with a panoramic view of the whole nailfold, facilitated by frame registration software [13].

Number of Fingers to Be Studied

Different investigators have studied different numbers of nailfolds (e.g. 10 nailfolds, 8 nailfolds and 1 nailfold [finger 4]). For example, ten fingers have been evaluated in the seminal study describing “normal” capillaroscopic appearances in a study population of 800 healthy subjects by using stereomicroscope [18]. On the other hand, in the screening of a patient with RP with the manual capillaroscopic techniques with qualitative assessment (see below), examination of eight fingers is usually recommended [6]. This is based on the fact that there may be a high variability in morphology between fingers in patients affected by a secondary RP. Of note, the thumbs are usually spared in secondary RP [19] and not evaluated.

Interestingly, it is noteworthy that preliminary study on semiautomatic nailfold capillaroscopy has recently demonstrated the ability through quantitative assessment (see below) to separate healthy controls and patients with primary RP from secondary RP due to SSc by evaluating only one finger (ring finger of nondominant hand) [13].

Interpretation

The capillaroscopic images can be analysed qualitatively and (semi)-quantitatively.

Qualitative Assessment

In qualitative assessment (= pattern recognition) an overall interpretation is given after commenting on the visibility of the image, the morphology of the capillaries, the density and dimensions of the capillaries and the architecture [20]. Pattern recognition is the same process that allows recognition of a familiar face or voice [18]. It readily allows the clinician to distinguish normal and non-specific changes (in patients with primary RP [see below]) from an abnormal capillaroscopy due to a secondary RP due to SSc (see below). NVC, dermatoscopy as well as preliminary (semi)-automated capillaroscopy have in common that they are all able to discern a normal capillaroscopy from the specific changes found in SSc through pattern recognition [13, 21, 22].

(Semi)-quantitative Assessment

In quantitative assessment measurements can be made of certain characteristics of individual capillaries. For example, the diameter of capillaries can be quantified [23, 24]. Notably, capillary diameters in patients with secondary RP due to SSc are significantly larger than those in primary RP or healthy controls [23]. Also the number (and other characteristics [see below]) of capillaries can be measured either manually or semi-automatically. These can be reported through scores (semi-quantitative assessment) or as numbers per unit of quantity (e.g. per mm) [10, 13, 23]. Of note, the number of capillaries per mm is the most powerful predictor between a primary and secondary RP due to a scleroderma spectrum disorder [23, 25]. A recent important preliminary development is the semi-automated quantitation of capillary characteristics, performed on images acquired using a computer-based system [13]. Next to being less time consuming than manual quantitation an additional advantage of this technique is the fact that repeat images over time from the same patient can be compared. The latter may be a quality that facilitates monitoring. Semi-automated quantitation (based on the following features: width of capillaries, tortuosity, derangement and intercapillary distance) identifies differences between patients with primary RP and those with SSc [13].

Manual quantification of capillaroscopic characteristics is used in secondary RP as biomarker and as outcome measure. In this way quantification has been used to predict development of future digital trophic lesions in patients with secondary RP due to SSc [8, 26, 27]. In addition, it has been used as outcome measure in trials with vasomodulating therapy in a patient population with RP [27–30].

Investigation of a Patient with RP: Role of Capillaroscopy

Early Distinction Between a Primary and Secondary RP Due to SSc

Medical doctors are frequently referred patients with RP, a frequent symptom in the general population. The challenge is to distinguish patients with a primary RP (not connected to any CTD) from patients with a secondary RP (due to a CTD). Literature attests through both cross-sectional and short- and long-term prospective follow-up that about 13.6 % of patients presenting with RP as the only initial symptom will develop a CTD [31, 32]. 12.6 % go on to develop SSc and only 1 % develops another CTD (such as systemic lupus erythematosus [SLE]) [31]. Consequently the key point in evaluating a patient with RP is to detect those who will further on develop SSc. In 1992 LeRoy and Medsger proposed criteria to distinguish primary from secondary RP due to SSc [5]. Key criteria for primary RP are to have a negative anti-nuclear antibody (ANA) factor and normal nailfold capillaries. Key criteria for a secondary RP due to SSc is to have specific capillaroscopic alterations (the scleroderma pattern) and the presence of SSc-specific antibodies. Retrospective validation of these criteria allows correct classification of a patient in one clinical consultation in 89 % [33]. A 20-year prospective study of 586 patients with only RP at baseline demonstrated a positive predictive value (PPV) of 79 % and a negative predictive value (NPV) of 93 % of these criteria at last follow-up [31]. Of note, capillaroscopy does not play a pivotal role in detecting CTD other than SSc in a patient population with merely the RP as presenting system (see below).

What Is Normal in Primary RP?

A normal capillaroscopic pattern, by qualitative assessment, is characterised by a homogeneous distribution of hairpin-shaped capillaries as a “comb-like structure”, with a density of between 9 and 14 capillaries per mm (Fig. 12.2) [17, 18]. Yet, there exists a wide intra- and inter-individual variation in a normal population. The manuscript by Andrade et al. described the range of normal in 800 healthy subjects [18]. These authors evaluated ten nailfolds per subject with the wide-field technique. Apart from the stereotype hairpin-shaped open loop, there are common subtle morphological variations in the distal row capillaries and additionally unusual distinctive morphological alterations that are considered as anomalies (= pathological findings) (see Table 12.1). Importantly, anomalies must occur isolated or in a very low prevalence within a subject in order to be able to interpret the image as still being normal. When anomalies occur in a high prevalence within a subject or when several types of anomalies occur together the odds are high that there is an underlying microangiopathy (secondary RP). In this way Andrade et al. showed that only 8 % of healthy subjects presented two types of anomalies and even less (1 % of healthy subjects) showed three types of anomalies, whilst a single anomaly occurred in 25 % of healthy subjects.

Fig. 12.2

Normal and non-specific changes in a patient with primary RP. Image: Finger 4 left. Description: qualitative assessment. Magnification: ×200. Morphology: Open, hairpin and crossing (dashed arrow). Dimensions: Within normal limits. Architecture and distribution: Capillaries are regularly arranged in a parallel fashion. Number: 8/mm (the grid width is exactly 1 mm). Interpretation: Capillary image with some non-specific changes (crossing). This patient was ANA negative suggesting (in combination with the capillaroscopic appearances) a diagnosis of primary RP

Table 12.1

Capillaroscopic findings in healthy subjects (after Andrade et al. [18]), wide-field technique

Stereotype open loop	Hairpin shape
Subtle alterations	Tortuous (the limbs are curled but do not cross)
	Crossed (the limbs cross each other once or twice)
	Cuticulitis (the limbs are not visible; only tiny red dots in high density are apparent)
Anomalies	Ectasia (limbs are moderately enlarged, about four times the normal width, or with the diameter of a limb >20 μm)
	Megacapillary (aneurysmatic loop, with the width of limbs ten times the normal one)
	Meandering (the limbs are crossed upon themselves or with each other several times)
	Bushy (the limbs originate small and have multiple buds)
	Bizarre (striking atypical morphology although not conforming to the four previous defined categories)

Of note with the videocapillaroscopic technique the above-described subtle alterations have been defined as being non-specific (see also below) [34]. Additionally, for simplicity the anomalies in morphology have been categorised as (neo)angiogenesis (see Table 12.2) [26].

Table 12.2

Definitions describing capillaroscopic characteristics with the wide-field and videocapillaroscopic technique [18, 26, 34]

What Are Pathognomonic Abnormalities in Patients with RP Due to SSc?

Patients with RP who have an underlying clinically recognisable (= with skin involvement) SSc show a very characteristic combination of capillary abnormalities in the nailfold, which can easily be assessed through qualitative assessment (= pattern recognition). Maricq et al. described with the wide-field microscope technique (magnification ×12–14) the scleroderma pattern [4]. This pathognomonic combination contains the following: a striking widening of all three segments of the capillary loop (arterial, venous and intermediate), loss of capillaries and disorganisation of the nailfold capillary bed. Many branched “bushy” capillaries may also be observed. Through quantitative assessment, a decreased capillary density has been shown to be the best predictor of a secondary RP due to a scleroderma spectrum (SDS) disease. More specifically, the loss of capillaries to a number of lower than 30 capillaries per 5 mm (= one nailfold) has a specificity of 92 % [25].

In 2000, Cutolo et al. qualitatively assessed the nailfolds of an SSc cohort of patients fulfilling the American College of Rheumatology (ACR) criteria for SSc with the NVC technique (magnification ×200) (Figs. 12.3, 12.4 and 12.5). According to the different proportions of the hallmark parameters of the scleroderma pattern (giants, capillary loss, haemorrhages and (neo)angiogenesis [definitions, see below]) Cutolo et al. defined three patterns “early”, “active” and “late” (see Table 12.3) [6].

Fig. 12.3

An early scleroderma pattern belonging to a patient with puffy fingers, RP and ANA+. Image: Finger 3 right. Description: Qualitative assessment. Magnification: ×200. Morphology: Open shape of capillaries. Presence of a haemorrhage (outside the grid). Dimensions: Giant (open down arrow) (cfr. measurement of transitional segment of the one marked capillary = 81 μm). Architecture and distribution: Slight derangement of capillary architecture. Number: 7/mm. Interpretation: The combination of minimal reduction of capillaries, haemorrhage and giant capillary is representative of the “early” scleroderma pattern. The patient meets the criteria for very early diagnosis of SSc

Fig. 12.4

An “active” scleroderma pattern belonging to a patient with diffuse cutaneous SSc. Image: Finger 2 right. Description: Qualitative assessment. Magnification: ×200. Morphology: Open shape of capillaries. Presence of haemorrhages (open triangle). Dimensions: Ectasia (dash), giant capillaries (open left headed arrow). Architecture and distribution: No derangement of capillary architecture. Number: 4/mm. Interpretation: The combination of reduction of capillaries, haemorrhage and giants is representative of the “active” scleroderma pattern

Fig. 12.5

A “late” scleroderma pattern in a patient with limited cutaneous SSc and digital ulcers. Image: Finger 4 left hand (b) Description: Qualitative assessment (a) Magnification: ×200. Morphology: Three neoangiogenetic capillaries (section symbol). Dimensions: Diameter of loops falls within the range of normal (<20 μm). Architecture and distribution: Derangement. Number: 3/mm. Interpretation: The combination of reduction of capillaries and ramification is characteristic of the “late” scleroderma pattern

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