Dr. Herrick has received consulting and speaking fees from Actelion and consulting fees from Pfizer (less than $10,000 each); and she has been an investigator in studies sponsored by United Therapeutics and MediQuest Therapeutics.
Raynaud's phenomenon (RP) is essentially an exaggerated vasospastic response to cold or emotion. In the classic triphasic response, the digits turn white (ischemia), then blue (deoxygenation), and then red (reperfusion) (Figure 1). When mild, RP is uncomfortable but has minimal impact on quality of life; this is the situation for many patients with primary (idiopathic) RP (1). At the other extreme, RP can progress to irreversible tissue injury with ulceration and sometimes gangrene; this occurs in a significant proportion of patients with underlying connective tissue disease, particularly systemic sclerosis (SSc; scleroderma)–spectrum disorders (2).
Key questions are whether we can identify those patients with RP who are at risk of progression to irreversible digital ischemia, and if so, whether there is any form of early intervention that will prevent such progression? The answer to the first part of the question is “yes.” The answer to the second part is “we don't know,” but recent advances in therapy suggest that with well-designed clinical trials we may have an answer in the next decade. In this review article, we will discuss advances in our understanding of RP and in the early detection of underlying connective tissue disease, with a focus on capillaroscopy. We will also discuss how advances in the diagnosis of complications, in the monitoring of microvascular disease, and in therapy over the last 6 years since our previous review (3) hold promise for prevention as well as for cure.
Why Raynaud's phenomenon?
Raynaud's is a phenomenon, not a disease per se. There are many possible causes, including SSc-spectrum disorders, extrinsic vascular obstruction as in thoracic outlet syndrome, hand–arm vibration syndrome, paraproteinemias, and certain drugs/chemicals (4). Although the pathophysiology of RP is not fully understood, it will differ between these underlying causes. For example, the pathophysiology of primary RP is likely to relate mainly to a functional vascular defect, whereas in cryoglobulinemia, increased blood viscosity will play a major role. This review article will concentrate on SSc-spectrum disorders and primary RP, because these are the conditions of most interest to the rheumatologist and in which the pathogenesis of digital ischemia has been most researched. The importance of primary RP is that it does not progress to irreversible digital ischemia; therefore, as rheumatologists, we need to understand what it is that sets primary RP apart from SSc-spectrum disorders.
In RP there is an imbalance between vasoconstriction and vasodilatation in favor of vasoconstriction. Abnormalities of the blood vessel wall, in the neural control of vascular tone, and in circulating mediators (including those produced by platelet activation, endothelial cells, and in response to oxidative stress) all contribute (5). They will be considered briefly under the headings of vascular, neural, and intravascular (although it must be stressed that these are false distinctions, because they all interrelate) with an emphasis on vascular, because it is in this area that most of the recent advances in diagnostics and therapeutics have been and are being made.
Vascular abnormalities in patients with RP may be purely functional (as is most likely the case in primary RP) or both functional and structural (as in SSc ). Functional abnormalities can occur via several different mechanisms, many of which involve the endothelium, including but not confined to the following:
1Impaired endothelial-dependent vasodilatation. There is now a considerable amount of evidence to support a defect in endothelial-dependent vasodilatation in SSc (6, 7), and some investigators have reported that this occurs also in primary RP (8).
2Reduced production of vasodilators. It is possible that a relative nitric oxide (NO) deficiency contributes to the pathogenesis of RP, although the situation is complex; NO can be overexpressed in SSc (9, 10), and regulation of NO may be abnormal (11).
3Increased vasoconstriction. This occurs for a variety of reasons, including increased production/expression of endothelin 1, a potent vasoconstrictor, in patients with SSc (12, 13); abnormalities in the renin–angiotensin system, resulting in imbalance in favor of angiotensin II, another potent vasoconstrictor (14); and abnormalities in signal transduction pathways in vascular smooth muscle (15, 16).
Regardless of what is the main driver of the functional microvascular changes, in patients with SSc, these changes are most marked in the digits (17).
Structural vascular abnormalities occur in both the microcirculation and the digital arteries of patients with SSc (18–20). Their pathogenesis is not fully understood, but endothelial cell abnormalities occur early (21), and it is likely that defective endothelial cell apoptosis, up-regulation of adhesion molecules, interactions between a large number of growth factors and cytokines, and pericyte activation all play a role. Both angiogenesis and vasculogenesis are defective in SSc (22, 23). In the microvasculature, the end result is that the number of capillaries is reduced, and those capillaries that are present are abnormal, often with very dilated loops. This distorted capillary architecture is well visualized by capillary microscopy (Figure 2).
There are likely to be both peripheral and central components in the neural control of vascular tone. In the periphery, impaired vasodilatation may result from reduced release of vasodilators, including calcitonin gene–related peptide, from nerve endings (24). Alpha2-adrenoceptor activation causes increased vasoconstriction. It is now recognized that the α2C-adrenoceptor may be responsible for cold-induced augmentation of α2-adrenoceptor activity. Flavahan and his group have conducted a series of experiments investigating the signaling pathways responsible for α2C-adrenoceptor expression; it is likely that both oxidative stress (25) and estrogen (26) increase α2C-adrenoceptor expression and thereby cold-induced constriction of cutaneous arteries, demonstrating how vascular, neural, and intravascular factors all interrelate.
Many circulating factors have been implicated in the pathogenesis of RP; this is especially true in patients with SSc. These circulating factors include platelet activation (27) (demonstrated by increased circulating levels of thromboxane and β-thromboglobulin), impaired fibrinolysis (demonstrated, for example, by elevated circulating levels of tissue plasminogen activator antigen) (28), white blood cell activation, reduced red blood cell deformability, increased viscosity (29), and oxidative stress (for review, see ref.5).
In patients with SSc, smoking is associated with the severity of digital ischemia (30). There are several possible mechanisms for this, including increased viscosity, impaired fibrinolysis, and the high free radical content of cigarette smoke. With the female preponderance of RP, hormonal factors have long been implicated but for reasons that remain unclear. An increase in α2C-adrenoceptor expression by estrogen as described above may provide a link here (26). Finally, genetic factors have been implicated in both primary RP and SSc (31, 32).
Primary or secondary Raynaud's phenomenon
The first question for the rheumatologist confronted with a patient with RP is “Why does this patient have Raynaud's?” If the patient has primary RP, he or she can be reassured and most likely discharged with a set of, recommendations but without the need for followup in secondary care. First, however, the rheumatologist must exclude secondary causes of RP.
LeRoy and Medsger proposed the following criteria for primary RP (33): episodic attacks of acral pallor or cyanosis, strong and symmetric peripheral pulses, no evidence of digital pitting, ulceration, or gangrene, normal nailfold capillaries, negativity (titer <1:100) for antinuclear antibodies (ANAs), and a normal erythrocyte sedimentation rate (ESR). The method of ascertainment of “normal nailfold capillaries” was unspecified. At present, many rheumatologists do not routinely perform nailfold capillaroscopy but examine the nailfold with the naked eye alone. Below, we will provide evidence in favor of capillaroscopy, which is supported by the proposal that RP together with abnormal nailfold capillaries are sufficient for a diagnosis of early SSc (34). More recently, the European League Against Rheumatism (EULAR) Scleroderma Trial and Research Group proposed another set of criteria (yet to be validated) for very early diagnosis of SSc (35). Either all 3 major criteria or 2 major and 1 additional criteria must be met, with the 3 major criteria being RP, the presence of antibodies (antinuclear, anticentromere, antitopoisomerase I) and abnormal results of diagnostic nailfold videocapillaroscopy. Although these recently proposed criteria require one other abnormal clinical or laboratory feature in addition to abnormal results of nailfold capillaroscopy for a diagnosis of SSc in a patient with RP, nonetheless they support a central role for nailfold capillaroscopy in the identification of early SSc.
Bearing these criteria in mind, the key points in the patient's history are whether there have been any digital ulcers (in which case RP is not primary) (1), and whether there are any features of connective tissue or other systemic disease. The examination should focus on the digits (looking for pitting, ulceration, sclerodactyly, and nailfold changes) and on the peripheral pulses, but as with the history, the clinician needs to be alert to the possibility of clues to an underlying systemic disease. Anemia, an elevated ESR, or ANA positivity (titer >1:100) also point to the possibility of RP being secondary. A chest or thoracic-outlet radiograph should be requested to look for a cervical rib if RP is confined to the upper limbs.
The clinical dilemma is that in a proportion of patients presenting with RP but without features of an underlying connective tissue disease, connective tissue disease will nonetheless develop later. Several investigators have conducted prospective studies addressing this issue, and a meta-analysis in 1998 (36), including 639 patients with primary RP followed up for 2,531 patient-years, showed the development of connective tissue disease in 12.5% of the patients, equating to a mean rate of ∼3 patients per 100 patient-years. Similar results were observed in a recent study (37) of 236 patients in whom primary RP was diagnosed: 2% of patients annually converted to “suspected secondary RP,” and 1% converted to secondary RP. In other words, >20% of patients “transitioned” over the followup period of >10 years (37). These findings suggest that the distinction between primary and secondary RP is by no means absolute, and indeed, it has previously been proposed, in a study that showed subtle capillary morphologic changes in patients with primary RP (38), that primary RP may be a form fruste of an SSc-spectrum disorder or at least represents a risk factor itself. So the next question is, will improvement in the techniques of predicting underlying connective tissue disease (and in this review we focus on capillaroscopy) translate into clinical benefit for patients by allowing early identification of those patients in whom disease evolves? A separate but related question is whether, among the group of patients with newly diagnosed connective tissue disease, the degree of nailfold capillary abnormality relates to prognosis, especially in terms of digital vascular disease.
Rationale for early clinical diagnosis of secondary Raynaud's phenomenon
Ten years ago, it could have been justifiably asserted that there was relatively little point in differentiating between primary RP and the very early stages of an SSc-spectrum disorder. This was because no disease-modifying treatment for SSc existed, and therefore early diagnosis might have achieved very little other than alarming the patient. Although no drug has been proven to modify either vascular abnormalities or fibrosis early in the disease course, it is now recognized that several currently available drugs have effects on vascular remodeling: angiotensin-converting enzyme inhibitors (39), prostanoids (40), and endothelin 1 receptor antagonists (41). Recently, improvements in nailfold capillaroscopic appearances have been reported after autologous hematopoietic stem cell transplantation (42, 43), suggesting that intense immunosuppression might also have effects on vascular remodeling. Especially in patients with limited cutaneous SSc, there is often a long lag period between the onset of RP and its diagnosis (44). This means that we need clinical studies of patients presenting with RP, including those with primary RP, undifferentiated connective tissue disease, and early SSc, looking for change over time (particularly with respect to the microvasculature as assessed by capillaroscopy) and predictors of change/progression over time, and leading to trials of early intervention with drugs that could potentially remodel the vasculature. Advances in capillaroscopy, described below, now make this a feasible option.
Capillaroscopic detection of the early microvascular alterations that are markers of secondary Raynaud's phenomenon
Nailfold videocapillaroscopy (NVC), an extension of the original widefield technique, can be regarded as the most valuable, safe, and inexpensive technique for detecting the early (initial) and advanced characteristics of microangiopathy in SSc, such as the morphologic changes in the nailfold that have been extensively described (e.g., giant capillaries, microhemorrhages, loss of capillaries, neovascularization, and avascular areas) (45, 46) (Figure 2). An advantage of NVC compared with the older widefield technique is its high magnification (200–600× compared with 12–14×). However, many investigators still use the widefield technique. Such capillary abnormalities are well recognized, when clinical and laboratory features of the disease are otherwise limited to RP (47).
For this reason, the microvascular alterations have been recently reclassified by Cutolo et al (48) into 3 defined and different NVC patterns that include an “early” pattern (few giant capillaries, few capillary microhemorrhages, no evident loss of capillaries, and relatively well-preserved capillary distribution), an “active” pattern (frequent giant capillaries, frequent capillary microhemorrhages, moderate loss of capillaries, absent or mild ramified capillaries with mild disorganization of the capillary architecture), and a “late” pattern (almost absent giant capillaries and microhemorrhages, severe loss of capillaries with extensive avascular areas, ramified/bushy capillaries, and intense disorganization of the normal capillary array) (48) (Figure 2). However, the marked increase in capillary size is the most characteristic feature of the nailfold capillary bed in early secondary RP (Figure 2). In particular, the detection of enlarged and giant capillaries, together with microextravasation (hemorrhage) of the red blood cells in the nailfold, most likely represents the first (initial) morphologic sign of the altered microcirculation in SSc.
The shape of the widened capillaries is largely heterogeneous, but giant capillaries with a homogeneous enlargement (diameter >50 μm) are an absolute marker of an SSc capillaroscopic pattern. This picture characterizes the early (initial) SSc capillaroscopic pattern (49, 50). As the pathophysiologic process of SSc progresses into fibrosis, the capillaroscopy analysis most likely reflects the effects of tissue hypoxia: massive capillary destruction, then increased loss of capillaries and avascular areas are observed, together with bushy capillaries indicating neoangiogenesis. This advanced stage of SSc is characterized by the late capillaroscopic pattern (48) (Figure 2). We accept that patients with the early capillaroscopic pattern may have had RP for many years; the term “early” was chosen because this pattern of change tends to occur initially and in patients with shorter disease duration than in those with active or late patterns. However, it must be recognized that these capillaroscopic patterns are descriptive, that there is inevitable overlap between patterns, and that further studies are indicated to examine changes in patterns over time.
To quantify the microvascular change, a practical system to score these capillaroscopic alterations in patients with SSc was recently proposed and validated (51, 52). The development of robust scoring systems is an essential prerequisite to longitudinal studies; although to date there have been few prospective studies examining nailfold capillary changes over time or in response to therapy, such studies are currently ongoing.
Recently, confirming a link between capillaroscopic markers and disease progression in SSc, Koenig et al (53) noted that in RP that evolves to definite SSc, microvascular damage (as measured using a stereomicroscope, 8–50× magnification) appears dynamic and sequential, while SSc-specific autoantibodies are associated with the course and type of capillary abnormalities (53). In this study, involving 586 patients who were followed up for 3,197 person-years, abnormal findings on capillaroscopy at baseline, together with an SSc-specific autoantibody, indicated a very high probability of definite SSc developing, whereas their absence ruled out this outcome (53). However, a transition to secondary RP, taking into consideration just the capillaroscopic markers of SSc, was observed in 14.6% of patients with primary RP over a mean period of 29.4 months (54).
Capillaroscopic links to laboratory markers in secondary Raynaud's phenomenon
With the increasing use of capillaroscopy for the differential diagnosis of RP and for the followup of patients with SSc, several studies have investigated possible links between microvasculature damage and specific laboratory markers of SSc.
One of the first studies to look for associations between capillaroscopic change and circulating markers demonstrated a correlation between soluble serum levels of the adhesion molecule E-selectin and capillary loss, especially in patients with early disease (within 48 months of diagnosis), suggesting that serum E-selectin levels might be a useful biochemical marker of disease activity in SSc (55). Serum levels of tissue kallikrein, acting on the microcirculation as a potent angiogenic agent, were higher in SSc patients with early and active capillaroscopic patterns compared with those with the late pattern (56). Interestingly, the highest endothelin 1 plasma levels have been detected in the more advanced stage of SSc microangiopathy, namely, the “late” NVC pattern, characterized by capillary loss and increased tissue fibrosis; this seems to support the involvement of endothelin 1 in the progression from microvascular to fibrotic SSc damage (57). Endothelin 1 plays an important role in SSc by causing vascular endothelial cell proliferation, vasoconstriction, smooth muscle hypertrophy, irreversible vascular remodeling in the lungs, and by promoting fibroblast synthesis of type I and type III collagen and fibronectin by a receptor-dependent mechanism (58).
Another study evaluating urinary concentration of F2-isoprostanes as a marker of oxidative stress in SSc patients showed a strong correlation of 8-iso-prostaglandin F2α levels with active and late capillaroscopic patterns (59).
Regarding the anti–endothelial cell antibodies (AECAs) that have been described in SSc, their clinical relevance is unclear; however, a recent study showed that AECAs were significantly more frequent in SSc patients with the late capillaroscopic pattern compared with the patients with early and active patterns (P < 0.05) (60). These data suggest that AECAs may have a role in the progression of endothelial damage in SSc, and that their presence, especially in high titers, should be considered as adjunctive risk factors for a more severe disease.
Concerning the anti–topoisomerase I (anti–Scl-70) antibodies and anticentromere antibodies (ACA), anti–Scl-70 were observed more frequently in patients with SSc showing the active and late patterns, whereas ACAs were observed especially in patients with the late pattern (61).
Table 1 summarizes the associations between the different laboratory parameters and the nailfold capillaroscopic pattern when these have been described in terms of early, active, and late SSc patterns.
Table 1. Associations between different laboratory parameters and early, active, and late SSc patterns of capillaroscopic abnormality*
Levels higher in patients with late pattern than in those with early or active pattern
In a very recent study already mentioned above, enlarged/giant capillaries, capillary loss, and SSc-specific autoantibodies independently predicted definite SSc (53). Those investigators reported associations between certain patterns of capillary abnormality and different specific autoantibodies. Anti–CENP-B and anti-Th/To antibodies predicted enlarged/giant capillaries; these autoantibodies and anti–RNAP III predicted capillary loss. Interestingly, each autoantibody was associated with a distinct time course of microvascular damage, as gauged by capillary enlargement or capillary loss. At followup, 79.5% of patients with one of these autoantibodies and abnormal findings on nailfold capillary microscopy at baseline had developed definite SSc (53). Patients with both baseline predictors (abnormal capillaroscopy and an SSc-specific autoantibody) were 60 times more likely to develop definite SSc.
In summary, several different laboratory variables have been shown to be associated with different patterns of capillary abnormality, providing further insights into disease pathogenesis. Further larger-scale studies, both cross-sectional and longitudinal, are required to confirm these associations.
Predictive value of capillaroscopic analysis of clinical complications in SSc
In the last few years, an impressive number of investigations have evaluated in SSc patients the association of nailfold NVC patterns with both demographic and clinical features. Almost all the studies revealed that SSc microangiopathy correlates with disease subset and the severity mostly of peripheral vascular, skin, and lung involvement; patients with the late pattern showed an increased risk of having active disease and of showing moderate/severe skin or visceral involvement compared with patients with early and active capillaroscopic patterns (62).
Skin ulcers are a common vascular complication of SSc and now seem to be recognized in association with the late NVC pattern, which is characterized by avascular areas. An association with trophic lesions and loss of capillaries, as assessed by semiquantitative scoring, has also been reported (63). In fact, loss of capillaries may be relevant in determining tissue hypoxia, and in patients with recent-onset RP, the appearance of rapidly progressive capillary loss may represent the first capillaroscopic evidence of severe SSc with destruction of microvessels (64). Very recently, in a study of 130 patients with SSc who were examined at the time of entry and after 20 months of followup, the diffuse cutaneous SSc phenotype with avascular areas on capillaroscopy represented, among other factors (e.g., increased IL-6), the major risk factor for ulcer development (65). Because the early detection of SSc patients who are at high risk of developing digital ulcers might allow preventive treatment of these complications with reduction of morbidity and social costs, a very recent study presented a capillaroscopic skin ulcer risk index that might predict the onset of new digital ulcers by using NVC analysis in patients with SSc (66). However, this index is complex and has not yet been validated. Easier methods to calculate prognostic indices are required and should soon be available.
Digital ulcers have been associated with significantly reduced blood velocity at the fingertips (67); in addition, SSc patients with the active and late NVC patterns showed decreased blood velocity (65.5% and 66.2% reduction, respectively) and, in particular, the reduced blood velocity was significantly associated with capillary ramification and capillary loss. Ideally, future studies examining associations between digital ulceration and nailfold capillaroscopic patterns should consider digital-tip ulcers and extensor surface ulcers (usually overlying contractures) separately, as was done in the analysis by Alivernini et al (65). This is because although both ischemia and fibrosis are likely to contribute to most SSc-related ulcers, the ischemic component is generally considered most prominent in digital-tip ulcers.
Regarding the predictive value of capillaroscopy in visceral involvement, a study from 1998 showed that reduced nailfold capillary density in SSc patients with established pulmonary arterial hypertension (PAH), might have possible pathogenic significance and may allow detection of this subset of patients (almost 20%) at an early stage in their disease progression (68). A more recent study showed that the association between ground-glass lung opacities and higher capillaroscopic avascular scores was particularly strong in SSc patients with a disease duration of ≤5 years (69). In particular, among these patients, ground-glass opacities were present in 14 of 19 patients with advanced capillaroscopic alterations but were absent in all 8 patients with mild or no capillaroscopic alterations (P < 0.001).
Very recently, the question of whether there are differences in capillary nailfold changes in SSc patients with and those without PAH was addressed in a larger study including patients with SSc both with and without PAH and also patients with idiopathic PAH (70). Capillary density was lower in patients with SSc and PAH compared with that in patients with SSc but without PAH (P = 0.001), but loop dimensions were equal. In comparison with idiopathic PAH, patients with SSc and PAH had reduced capillary density (P < 0.001) and larger loop dimensions (P < 0.001). Capillary density in healthy control subjects was significantly higher when compared with that in patients with SSc without PAH, SSc patients with PAH, and patients with idiopathic PAH. Interestingly, capillary density negatively correlated with mean pulmonary arterial pressure at rest in patients with SSc and PAH (P = 0.039) and in patients with idiopathic PAH (P = 0.001) (70). Therefore, a reduction in nailfold capillary density (late SSc pattern) correlates with the severity of PAH in both SSc and idiopathic PAH. The study by Hofstee et al (70) measured capillary density and dimensions from a computerized mosaic of the nailfold (71), thereby allowing correlations between continuous variables.
As with laboratory markers, further larger-scale studies, both cross-sectional and longitudinal, are required and are ongoing to examine further the associations between capillaroscopic findings and other parameters of disease.
Implications for therapy
Current treatments for RP are often ineffective. The ultimate challenge to clinicians with an interest in RP, particularly SSc-related RP, with its propensity to lead to irreversible tissue injury, is to identify a drug that will prevent progression of or (better still) remodel the digital microvascular abnormalities that, as described above, lead to impaired perfusion and most probably hypoxia.
Capillaroscopy has a role to play here. As mentioned above, several currently available drugs are now known to have effects on vascular remodeling. In addition, several exciting new lines of therapy, for example therapies targeting signal transduction pathways involved in cold-induced vasospasm (16), deserve further research. Therefore, although we know that intravenous prostanoids are effective in SSc-related RP (72, 73), and that bosentan, an endothelin 1 receptor antagonist, can prevent SSc-related digital ulceration (74), what we need to know is whether early intervention with drugs known to have vascular remodeling potential might prevent disease progression. In other words, can we identify a vascular disease-modifying agent for use especially in early disease? By more widespread use of capillaroscopy, it should be possible to identify patients with different levels of severity of digital vascular disease (including early disease) to recruit into clinical trials in which capillaroscopy will be one of several or even the major outcome measure. The right time for this is now, because of the following: 1) the current availability of different drugs to be put to the test in clinical trials; 2) increased international networking of clinicians with an interest in RP, as evidenced by recent large-scale multicenter trials (74–76), and the recent development of different methods, both semiquantitative and quantitative, of measuring capillaroscopic change over time (51, 71, 77). The ability to exchange images between centers electronically will allow standardization of analysis.
We believe that clinical trials of early intervention for SSc-related RP are therefore now feasible and will be facilitated by more widespread use of capillaroscopy internationally.
Although most of the recent advances in capillaroscopy relate to high-magnification videocapillaroscopy, which allows not only detailed analysis of the nailfold capillaries but also image storage and the ability to track change, it is accepted that many rheumatologists do not currently have access to this technology. Nailfold capillaries can be visualized, albeit in much less detail, using an ophthalmoscope (78) or dermatoscope (79), both of which are handheld and therefore easy to use in the outpatient clinic. Baron et al reported “moderate to substantial” reliability for dilated and giant capillaries with both the ophthalmoscope and the dermatoscope (80), and a more recent study showed good interobserver and intraobserver reliability of dermoscopy, using a 0–3-point rating scale for normal, mildly abnormal/suspicious, definitely abnormal, and grossly abnormal capillaries (81). Therefore, handheld devices are likely to be useful in the clinical setting for identifying patients with widened capillary loops but are less likely to be useful in the research setting and during patient followup, when more detailed assessment and quantification of abnormality are important. Further research is required to establish the sensitivity and specificity of handheld devices in comparison with videocapillaroscopy.
RP is often the earliest clinical symptom of digital microcirculatory change and can be considered one of the risk factors for the development of a connective tissue disease. NVC detects the early microvascular abnormalities that characterize secondary RP, and the changes are quantifiable. Combining the power of capillaroscopy for the early diagnosis of secondary RP, its predictive value for clinical complications of SSc, and its potential for monitoring disease progression/treatment response, makes it an important noninvasive tool for both the clinician and the researcher. In addition, recent advances in targeted therapies for SSc suggest that with well-designed clinical trials, we are now well placed to identify effective disease-modifying drugs. The monitoring of one rheumatologist in training indicated that novices can quickly learn, through an intensive self-teaching program under the supervision of an expert, how to use computerized videomicroscopy to conduct capillaroscopy studies (82). The facts that expertise in the technique can be rapidly acquired (EULAR courses have been available for several years, and in 2010 a new study group for capillaroscopy was established by the American College of Rheumatology) lend further weight to the assertion that videomicroscopy is likely to gain further momentum as a clinical and research tool.
Both authors were involved in drafting the article or revising it critically for important intellectual content, and both authors approved the final version to be published.