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Introduction

  1. Top of page
  2. Introduction
  3. Use of Capillaroscopy in Rheumatology
  4. The Future of Capillaroscopy in Rheumatology
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

In 1973, Maricq and LeRoy published the first article describing the specific capillaroscopic pattern in systemic sclerosis (SSc; scleroderma) (1). This was the first in a series of studies that contributed to the initial spread of the technique and highlighted the remarkable diagnostic potential of in vivo capillary microscopy in detecting scleroderma microangiopathy (1–6).

However, several years later, despite its undisputed diagnostic value, the growth in capillaroscopy had only partially fulfilled its initial potential and had failed to make a significant impact in rheumatology. This may be related to the fact that capillaroscopic findings of the so-called scleroderma pattern have only been more recently included in the classification criteria of SSc (7–9), in the last few years. A Medline search performed with the words “capillaroscopy” and “nailfold capillary microscopy” revealed that there were 717 articles published between 1980 and 2008, with an average of 25 articles per year. Fewer than 200 papers that focused on rheumatic diseases were found, and only 123 of those published were in rheumatology journals. Therefore, one reason for the limited use of capillaroscopy in rheumatology may be the scarce dissemination of its value in rheumatology venues.

Although capillaroscopy performed using photographic equipment is generally economical, it is a complex and time-consuming process. The recent availability of images obtained using digital systems has led to a renewed interest toward videocapillaroscopy, and makes this technique more reliable and user-friendly. We consider videocapillaroscopy to be one of the best diagnostic tools for the early recognition of SSc and related conditions. In this article, we will describe the use and value of capillaroscopy in rheumatology.

Use of Capillaroscopy in Rheumatology

  1. Top of page
  2. Introduction
  3. Use of Capillaroscopy in Rheumatology
  4. The Future of Capillaroscopy in Rheumatology
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

First-line examination of patients with Raynaud's phenomenon.

According to epidemiologic surveys, Raynaud's phenomenon (RP) has a prevalence ranging from 2% to 22% (6, 10–12). There is substantial agreement regarding the fact that every patient with RP should undergo a capillaroscopic examination (6, 7, 11), which may significantly assist in characterizing the clinical and evolving profile (11). Capillaroscopic findings associated with RP may vary, ranging from a normal pattern to abnormalities that show microvascular involvement, including microhemorrhages, irregularly enlarged loops, megacapillaries or giant loops, neoangiogenesis, architectural derangement, and loss of capillaries (1–3, 6).

In a patient with clinically isolated RP, even a single morphologic abnormality such as a megacapillary or an irregularly enlarged loop (especially with an aneurysm-like appearance) should alert the physician to the possibility of an underlying scleroderma spectrum disorder (secondary RP) (11, 12). In secondary RP, the presence of abnormalities that characterize the scleroderma pattern (Figure 1) supports a high specificity and a positive predictive value for the diagnosis of SSc and related disorders, more than a positive antinuclear antibodies test. Similarly, a normal capillaroscopic pattern is likely to indicate primary RP (11, 13, 14). Other adjunctive tests that may have prognostic and diagnostic value in clinical use for detecting secondary RP include laser Doppler flowmetry, thermography, and finger systolic blood pressure (5, 11).

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Figure 1. Nailfold capillaroscopy in secondary Raynaud's phenomenon. Note the irregularly enlarged loops, megacapillaries, and angiogenesis (arrows). (Original magnification × 200.)

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Transition from primary to secondary RP.

Patients with primary RP should undergo a careful capillaroscopic analysis every 6 months in order to detect, at the earliest time and in the most reliable manner, the transition to the secondary form of RP (15). The combination of capillaroscopy with laser Doppler imaging of the nailfold microcirculation seems to be significant in distinguishing whether a reduced blood flow is due to primary or secondary RP (16, 17).

In a recent investigation, 20% of patients initially diagnosed as having primary RP were found to have transitioned to either suspected secondary RP or definitive secondary RP during an average followup period of 10 years (18). The annual incidence of transition to suspected secondary RP or definitive secondary RP was 2% and 1%, respectively. Although capillary microscopy was considered in this study, its use was not fully analyzed, and its relevance for the diagnosis was partly underestimated.

The importance of capillaroscopy for identifying RP patients at high risk for the development of a scleroderma spectrum disorder has recently been addressed (6) using a prognostic model based on a weighted combination of different capillaroscopy parameters. In an additional study, 129 subjects were referred to an outpatient unit for analysis of primary RP (16). Based on the appearance of the patterns on nailfold videocapillaroscopy, 19 (14.6%) of the patients were classified as having secondary RP over a mean ± SD followup period of 29 ± 10 months. Interestingly, 4.6% of these patients had exhibited a normal capillaroscopic pattern at baseline (transition from normal to altered pattern observed in a mean ± SD of 42 ± 30 months) and 10% had minimal and nonsignificant microvascular alterations between the time of primary and secondary RP.

Early diagnosis of SSc.

Capillaroscopy can be regarded as the most valuable technique for detecting the early characteristics of microangiopathy in SSc, such as the morphologic changes in the nailfold that have been extensively studied including enlarged loops, megacapillaries, neovascularization, loss of capillaries, architectural disruption of the nailfold microvascular network, and avascular areas (1–6, 12, 19, 20) (Figure 2). Such capillary abnormalities can be recognized, even in the early stages of SSc, when clinical features of the disease are only limited to RP. Microvascular alterations have been reclassified into 3 defined and different patterns (20), which include an early pattern (few enlarged/giant capillaries, few capillary hemorrhages, no evident loss of capillaries), an active pattern (frequent giant capillaries, frequent capillary hemorrhages, mild disorganization of the capillary network), and a late pattern (irregular enlargement of the capillaries, few or absent giant capillaries, hemorrhages, and extensive avascular areas).

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Figure 2. Nailfold capillaroscopy in systemic sclerosis. A–D, Features of definitely enlarged loops. E, Disorganization of the nailfold capillary, along with prominent features of neovascularization (arrows). F, Loss of capillaries. (Original magnification × 200 in AD; × 100 in E and F.)

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A marked increase in capillary size is the most characteristic feature of the nailfold capillary bed in SSc (Figures 2A–D). The shape of the widened capillaries is largely heterogeneous, and there is no general agreement about the definition of loop enlargement (20–25). A practical system to score these microvascular alterations in scleroderma patients has recently been proposed by Sulli et al (26).

Differential diagnosis of the scleroderma-related conditions.

Capillaroscopy should be performed on all patients with RP in order to support or exclude an association with a scleroderma spectrum disorder (SSc, dermatomyositis [DM], and mixed connective tissue disease [MCTD]) (27). The presence of an indicative expression of a scleroderma microangiopathy should alert the physician to the presence of a systemic disorder (28).

In patients with DM, capillaroscopic abnormalities may be similar to those seen in patients with SSc, such as architectural derangement of the nailfold capillary network and prevalent features of marked angiogenesis (12, 29). Nailfold capillary abnormalities included within the scleroderma-like pattern can also be detectable in primary Sjögren's syndrome, especially when associated with RP (30), and in undifferentiated connective tissue disease (CTD) (21, 22, 31).

A capillaroscopic examination should be performed in patients with morphea and eosinophilic fasciitis, which is usually characterized by a normal pattern (32).

Early detection of severe microangiopathy in SSc.

Progressive capillary loss characterizes the microvascular involvement in SSc (Figure 2F); it also may be relevant in determining critical tissue hypoxia, and can serve as a warning for the potential development of avascular areas (12). Capillary loss has been associated with more extensive skin and/or visceral involvement and a poor prognosis (12, 33, 34). As mentioned above, the different SSc patterns are now well recognized, with the late pattern indicating the late stages of SSc (Figure 3).

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Figure 3. Normal capillary patterns (top left), and patterns seen in scleroderma. Early (top right): few giant capillaries (G), and microhemorrhages (H). Active (bottom left): increased number of giant capillaries and microhemorrhages, together with loss of capillaries (L). Late (bottom right): dramatic loss of capillaries, neoangiogenesis (N), and fibrosis (F).

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The definition and classification of avascular areas and capillary loss are not clear. However, a deletion area (or a discrete avascular area) is defined as the loss of >2 consecutive capillaries in the distal row (35) or as the absence of 3 consecutive capillary loops (6). Furthermore, avascular areas have in recent years been classified as moderate (33–66%) or severe (>66%) (36). Even if the progression of capillary loss is thought to be related to the duration of RP (20), avascular areas can represent the first dramatic capillaroscopic finding in recent-onset SSc, especially in men with very aggressive disease (12). A scoring system for the scleroderma abnormalities (which comprises loss of capillaries) is now available, and it may also help in the followup of scleroderma patients (26).

Therapy monitoring.

There is growing interest in the use of capillaroscopy for therapy monitoring. Capillary changes first described post-therapy are related to dynamic studies, in which the parameters used are the variations of blood flow and capillary permeability. A single oral administration of nifedipine (10 mg) has demonstrated a prompt antagonist effect on the cold-induced reduction of capillary permeability in patients with SSc (37).

Conversely, other studies reported morphologic modifications and nailfold loop changes following vasoactive therapy. A decreased capillary loss was observed after administering cyclosporin A and intravenous iloprost during an open, double-arm trial of 20 patients with SSc chosen randomly to receive either treatment with iloprost alone or iloprost in association with low-dose long-term cyclosporin A (38). The development of nailfold microvascularization, characterized by an increase in the loop number and a reduction in avascular areas, was described in 4 patients with SSc after a 3-year treatment sequence with iloprost (39). Furthermore, a significant decrease in severe avascular areas was observed in 16% of patients with MCTD treated with iloprost during a sequential evaluation of ∼3 years (24).

The development of new computer-based systems, specifically nailfold videocapillaroscopy, allows the visualization of a single loop image. When applied to longitudinal studies and clinical trials, this capability may improve reproducibility by providing the ability to guarantee examination of the same capillaries at different points in time (40).

Most recently, nailfold videocapillaroscopy analysis has been used to evaluate the effects of autologous hemopoietic stem cell transplantation (HSCT) in patients with severe diffuse SSc. Three months after HSCT, the nailfold videocapillaroscopy pattern changed from late to active, showing frequent giant capillaries and hemorrhages, absence of avascular areas, and angiogenetic phenomena (41). One year later, microvascular abnormalities still showed the active pattern, therefore indicating that HSCT with high-dose cyclophosphamide (1 gm/month for 6 months) may promote vascular remodeling. This effect must be confirmed by additional studies, but the initial results suggest the prognostic ability of nailfold videocapillaroscopy in monitoring patients after HSCT.

Assessment of microvascular involvement in other autoimmune rheumatic disorders.

The main capillaroscopic abnormalities described in patients with systemic lupus erythematosus (SLE) include increased tortuosity, loop elongation, enlarged and/or branching loops, and increased visibility of the subpapillary venous plexus, although in ∼50% of patients the capillaroscopic pattern is similar to that of healthy subjects (24, 42). Nailfold abnormalities, especially enlarged loops and capillary loss, have been correlated with the presence of lung involvement (42). In a subgroup of SLE patients, scleroderma-type findings were found with the simultaneous presence of RP and anti–U1 RNP antibodies (43).

Microvascular alterations were found in patients with antiphospholipid syndrome and anticardiolipin antibody–positive SLE patients, suggesting direct damage of the vascular endothelium is triggered by anticardiolipin antibodies (44). Symmetric microhemorrhages at the nailfold were present mainly in patients with both serum IgG and IgM anticardiolipin antibodies, with marked microvascular damage related to the occurrence of thrombotic manifestation (45). Patients with rheumatoid arthritis (RA) showed evidence of capillaroscopic abnormalities of uncertain significance, such as elongated loops (46). When clearly evident features of microangiopathy are present, a careful followup examination is advisable in order to identify any possible relationship between capillaroscopic abnormalities and disease subsets and/or overlap with other CTDs (32).

A reduction in loop length would distinguish patients with psoriatic arthritis from those with RA (46). This has not been subsequently confirmed, despite the possible occurence of dwarf loops in patients with psoriatic arthritis (47). The fact that it is unusual to find elongated loops even in patients with psoriatic arthritis is further confirmation that capillary length is not specific proof of microangiopathy (47). Conversely, capillaroscopy performed on the psoriatic plaques reveals considerable features of angiogenesis (tortuous, coiled ball, branching loops) and an increase in capillary diameter that appears to be related to the intense metabolic activity of the skin (48). Patients with mixed cryoglobulinemia demonstrate various nailfold microcirculatory changes, often clustered in a pattern of abnormally oriented short capillaries and neoangiogenetic phenomena, more evident in nephritic patients (49). Therefore, capillaroscopy might help to detect the microvascular involvement in several CTDs.

The Future of Capillaroscopy in Rheumatology

  1. Top of page
  2. Introduction
  3. Use of Capillaroscopy in Rheumatology
  4. The Future of Capillaroscopy in Rheumatology
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

Capillaroscopy represents the most reliable tool for the early differential diagnosis between primary and secondary RP, even in the absence of other clinical symptoms of an associated CTD.

Quantifying nailfold microvascular alterations is complex. However, as mentioned previously, a novel scoring system is now available and the lack of reproducibility of the capillary measurement might be of less concern to rheumatologists (26). Nevertheless, the development of a shared scoring method involves a multistep process in which feasibility, reliability, validity, and responsiveness should be evaluated in ongoing multicenter trials using appropriate statistical analysis. This new system should improve the application of the capillaroscopic technique in longitudinal studies and should have the potential of being a valuable outcome measure for microvascular disease/involvement in clinical assessment (40).

The traditional approach to capillaroscopy is frequently based on the use of optical instruments (macrophotography, stereomicroscopy) that guarantee only an overall evaluation of the entire nailfold area (widefield capillaroscopy). In addition to being time consuming, this procedure limits the quality of analysis and the realization of high- quality material. However, the availability of new computer-driven videomicroscopy systems has greatly simplified the acquisition, measurement, and recording of images of excellent quality (32, 40). Digitally stored images, with the consequent option of immediate printing for reports and/or saving onto media support, can be sent via the Internet for telediagnosis and teleconsultation, therefore contributing to the spread of the technique.

The teaching and training of capillaroscopy to rheumatologists was a difficult issue and was neglected for years. Previously, education and practice in capillaroscopy did not follow standardized models and were a result of unplanned initiatives (self-study). However, capillaroscopy courses have more recently been provided by international faculties, such as the European League Against Rheumatism (EULAR) full-immersion courses that were held in Genoa, Italy in 2004, 2006, and 2008. In 2008, SSc was indicated as an “orphan disease” of prominent interest for EULAR. The requirement of a standardized training curriculum and a recognized training program for capillaroscopy is now being considered by the Educational and Training Committee of EULAR, in association with the European Consortium for the Study of Scleroderma.

Previously, capillaroscopic findings of the scleroderma pattern were not included in the classification criteria of SSc, and only after 2000 have they been included in published classification criteria (7–9, 50). In 2001 the sensitivity of the American College of Rheumatology (ACR) criteria to identify patients with limited disease was found to be improved with the addition of nailfold capillary abnormalities and visible telangiectasias (from 34% to 89%) (51). More recently, 101 SSc patients were analyzed for the same purpose. Of these, 68 (67%) met the ACR classification criteria. The sensitivity increased from 67% to 99% with the addition of the nailfold capillary abnormalities identified using a simple dermatoscope and visible telangiectasias (52). The ACR classification criteria for SSc lack sensitivity for the diagnosis of early disease. However, this may be significantly improved with the inclusion of variables such as the detection of a well-recognized scleroderma pattern. This represents the real target of the capillaroscopic analysis in RP patients (53, 54).

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Introduction
  3. Use of Capillaroscopy in Rheumatology
  4. The Future of Capillaroscopy in Rheumatology
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

Dr. De Angelis had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. De Angelis, Grassi, Cutolo.

Acquisition of data. De Angelis, Cutolo.

Analysis and interpretation of data. De Angelis.

Manuscript preparation. De Angelis.

REFERENCES

  1. Top of page
  2. Introduction
  3. Use of Capillaroscopy in Rheumatology
  4. The Future of Capillaroscopy in Rheumatology
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES