Discovery Medicine, volume 12, Number 66, Pages 413-418, November 2011
Abstract: Purpose of the Study: The aim of the studywas to evaluate capillaroscopic pattern in systemicsclerosis (SSc) patients and its association with dis-ease duration as well as with presence of digitalulcers.
Patients and Methods: Thirty six patients with SScwere included in the study. The severity ofRaynaud’s phenomenon (RP) at the hands wasassessed with VAS (100mm), and the presence of dig-ital ulcers at the hands was documented. Nailfoldcapillaroscopy was performed by a videocapillaro-scope.
Results and Discussion: RP was found as a clinicalsymptom in 100% (36/36) of the examined SScpatients. In SSc patients with a duration of the dis-ease of less than 3 years, an early phase “scleroder-ma type” capillaroscopic pattern was found in 50%(5/10) of the cases. In the group of SSc patients witha duration of the disease of more than 3 years, latephase scleroderma type capillaroscopic pattern wasfound in 26.9% (7/26) of the cases, which was char-acterized by the presence of extensive, “desert-like”avascular areas and neoangiogenic capillaries.Scleroderma type capillaroscopic pattern was foundin 97.2% (35/36) of the cases. Digital ulcers at thehands were found in 36.1% (13/36) of the patients.In 100% of those patients with digital ulcers (13/13),
an active type scleroderma like pattern wasobserved, which is characterized by the presence offrequent giant capillaries, hemorrhages, and avas-cular areas. An active type scleroderma like patternwas found in 47.2% (17/36) of the patients withoutdigital ulcers.
Conclusion: The data show that the presence of dig-ital ulcers at the hands of SSc patients is stronglyassociated with an active type scleroderma like cap-illaroscopic pattern. Observation of an active typescleroderma like pattern in patients without digitalulcers may therefore be used as a predictor for thedevelopment of trophic changes in the future, anindication for vasoactive medication for the preven-tion of the development of digital ulcers, and as anadditional objective method for the evaluation ofdisease activity score in SSc. [Discovery Medicine
12(66):413-418, November 2011]
Introduction
Raynaud’s phenomenon (RP) is one of the most com-mon symptoms in systemic sclerosis (SSc) with a fre-quency of approximately 90-95% and is usually the ini-tial symptom that precedes other features of the diseaseby years (Block and Sequeira, 2001; Lukac et al., 1985;Seibold and Steen, 1994). RP in SSc is severe and oftenpresents with digital ulcers. The female to male ratio ofthe patients is 4:1 (Seibold and Steen, 1994). The capil-laroscopic pattern in SSc is specific and is characterizedby the presence of dilated and giant capillaries, hemor-rhages, avascular areas, and neoangiogenic capillaries.It has been described for the first time by Maricq et al.(1980) and is called “scleroderma” type capillaroscopicpattern (Maricq et al., 1980). This specific capillaro-scopic pattern is found in a large number of cases with
Capillaroscopic Findings in Systemic Sclerosis
-- Are They Associated with Disease Duration
and Presence of Digital Ulcers?
SevdAlINA lAmbovA ANd Ulf müller-lAdNer
Sevdalina Lambova, M.D., is at the Clinic of
Rheumatology, Department for Propaedeutics of
Internal Medicine, Medical University, Plovdiv, Bulgaria.
Ulf Müller-Ladner, M.D., is at the Department for
Internal Medicine and Rheumatology, Justus-Liebig
University Giessen, Giessen, Germany and
Department for Rheumatology and Clinical
Immunology, Kerckhoff Clinic, Bad Nauheim, Germany.
overt scleroderma (83-93%) (Maricq et al., 1983;Cutolo et al., 2005). Bergman et al. (2003) found thistype of specific capillaroscopic changes in 70.4%(19/27) of examined SSc patients. Nagy and Czirjac(2004) found it in 87.5% of patients with diffuse SScand in 61.6% of patients with a limited form of SScamong the 102 SSc patients examined. Maricq et al.(1983) described two types of capillaroscopic changesin SSc — the “active” and “slow” patterns. Extensiveand confluent avascular areas and neovascularizationare supposed to reflect activity and progression of thedisease (called active capillaroscopic pattern). In con-trast, the presence of giant capillary loops with minimalloss of capillaries is typical for the forms of the diseasewith a lower activity (called slow capillaroscopic pat-tern). Maricq (1986) found that some of the parametersof this pattern can also be observed in a group of scle-roderma spectrum disorders, e.g., mixed connective tis-sue disease, undifferentiated connective tissue disease(UCTD), overlap syndromes, and dermatomyositis(DM), and have defined these findings as “scleroderma-like” capillaroscopic pattern.
Cutolo et al. (2000) described three phases of capillaro-scopic changes in SSc:
1. An “early” phase — appearance of a few dilatedand/or giant capillaries and a few hemorrhages. In thisphase, the distribution of the capillaries is relativelypreserved without loss of capillaries. These findings areof crucial importance for the early diagnosis of SSc.
2. An “active” phase — there are large numbers of giantcapillaries and hemorrhages. In addition, a moderateloss of capillaries, slight derangement, and diffuse per-icapillary edema can be found.
3. A “late” phase — it is characterized by severe loss ofcapillaries with extensive avascular areas, bushy, andramified capillaries, and more than one capillary loop ina dermal papilla, which are the morphological conse-quence of the defective neoangiogenesis (Cutolo et al.,2000).
The above-described capillaroscopic changes in SSchave been confirmed histologically by Silver et al.(2005).
A relationship between capillaroscopic changes and thetype of SSc, its activity, and the visceral organ involve-ment has been proposed (Maricq et al., 1983; Sato et al.,2009), but not all investigators agree with this proposal(Lovy et al., 1985). Severe capillary loss was noticed tobe more common in patients with diffuse SSc. Amongthe examined 105 SSc patients (50 with the limited SSc
form and 55 with the diffuse form), dilated capillarieswithout loss of capillaries were found more frequentlyin patients with limited SSc (42.0%) than in patientswith the diffuse form of the disease (10.9%) (Ostojicand Damjanov, 2006).
Digital ulcers are a common complication in SScpatients. Capillaroscopic findings for the prediction ofthe development of digital ulcers in SSc are not welldefined. Alivernini et al. (2009) speculated on a possi-ble association between the development of ulcerationsand the presence of avascular areas at the capillaroscop-ic examination. Sebastiani et al. (2009) found a correla-tion between capillaroscopic changes and the develop-ment of digital ulcers in 120 SSc patients. A significantassociation between the presence of digital ulcers andthe lower number of capillaries in the distal row, as wellas with a higher number of megacapillaries and a high-er loop diameter, was observed. A capillaroscopic indexfor predicting the development of digital ulcers in SScpatients has been proposed (Sebastiani et al., 2009).
Purpose of the Study
The aim of the study was to evaluate capillaroscopicpattern in SSc patients and its association with the cuta-neous involvement, disease duration, as well as with thepresence of digital ulcers.
Patients and Methods
Thirty six patients with SSc, diagnosed according to thecurrent American College of Rheumatologists (ACR)classification criteria (Masi et al., 1980), were includedin the study: 30 patients with limited SSc, 5 with diffuseSSc, and 1 with overlap syndrome; 30 female and 6male patients with a mean age of 56±14 years (range of30-76 years). The severity of RP in the hands and feetwas assessed with visual analogue scale (VAS)(100mm) by the physician and the patient. The patientswere asked by the physician to evaluate the severity andfrequency of RP in the last month according to the dis-ability that vasospastic attacks cause to their everydayactivities.
The presence of digital ulcers of the hands and the feetwas documented. Skin score of the fingers and feet wasassessed by the scale used for evaluation of Rodnanskin score: 0, uninvolved skin; 1, mild; 2, moderate;and 3, severe thickening (Clements et al., 1995).Nailfold capillaroscopy was performed using a video-capillaroscope Videocap 3.0 (DS Medica, Italy).Measurements were performed with the software pro-gram of the device and all the measurements were madein millimeters (mm).
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Capillaroscopic findings in Systemic Sclerosis
The following capillaroscopic parameters were evaluat-ed: distribution, shape of capillaries, diameter of thearterial and the venous limb of the capillary loop, cap-illary length, mean capillary density, presence of avas-cular areas, hemorrhages, and neoangiogenesis. Thecapillary loops in most areas of the human body are per-pendicular to the skin surface, while at the nailfold theybecome parallel to the skin surface. This allows capil-laries at the distal row to be visualized at their wholelength. Normally capillaries of the nailfoldare hair-pin or U-like shaped. They follow aregular distribution with a single capillaryloop in each dermal papilla. Every singlecapillary loop consists of a thinner arteriallimb, a wider venous limb, and a connectingpart between them — an apical loop.Capillaries were classified as being dilatedwhen they have a diameter of the arteriallimb greater than 0.015mm or venous limbgreater than 0.020mm. Micro-vessels, eitherarterial or venous limb, with a diametergreater than 0.050mm were classified asgiant capillary loops. The mean diameter ofthe arterial limb and that of the venous limbwere calculated as a mean value of the arte-rial and venous limbs at their three widestparts, respectively. The length of the capil-lary loop was measured as the distancebetween the papillary plexus (if visible) orthe visualized base of the capillary loop andthe apical part. The mean capillary lengthwas calculated as a mean value of the threelongest capillaries. Those capillary loopswith a length greater than 0.300mm wereclassified as elongated capillary loops.
The hemorrhages are the extra capillarybrown aggregations of erythrocytes. Themean capillary density was calculated as anumber of capillary loops in the distal rowper 1 mm. The avascular areas were definedas a distance between two adjacent capillaryloops from the distal rows greater than0.500mm or greater than 0.300mm in theproximal area. Meandering capillaries,namely, presence of more than one capillaryloop in a single dermal papilla, and ramifiedand bushy capillaries are the characteristicfeatures of neoangiogenic capillaries(Schmidt et al., 1997). Twenty two healthyage- and sex-matched individuals were usedas healthy controls. The mean age of thehealthy controls was 51±12 years, with 19females and 3 males (p>0.05 compared to
the group of SSc patients in this study).
For statistical analysis of the data, variation analysis, t-criterion of V. Goset (Student-Fisher), and c-square testwere used. The study has been approved by the localethical committee and all patients signed an informedconsent. Results are shown as mean±standard devia-tion. We considered p<0.05 as being statistically signif-icant.
Figure 1. Scleroderma type capillaroscopic pattern, an early phase.D, dilated capillaries; G, giant capillaries; H, hemorrhages.
Figure 2. Scleroderma type capillaroscopic pattern, an active phase.G, giant capillaries; AA, avascular areas.
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Capillaroscopic findings in Systemic Sclerosis
Results
RP was found as a clinical symptom in 100% (36/36) ofthe examined SSc patients. “Scleroderma” type capil-laroscopic pattern with dilated and giant capillaries,hemorrhages, avascular areas, and neoangiogenesiswas found in 97.2% (35/36) of the cases.
The mean diameters of the arterial (0.035±0.013mm)
and the venous limb (0.053±0.021mm) in SSc were sig-nificantly wider as compared to the respective values inhealthy controls (0.012±0.001mm for the arterial limband 0.017±0,001mm for the venous limb) (p<0.05).The mean length of the capillary loop(0.284±0.109mm) was found to be significantly longeras compared to that in healthy controls(0.199±0.072mm) (p<0.05). The mean capillary densi-
ty in SSc patients (5.11±1.72 capillaries/mm;range of 4-10) was found to be significantlylower as compared to that in healthy subjects(10.3±0.59 capillaries/mm, range of 10-12)(p<0.05). A prominent subpapillary plexuswas found in 17.0% (8/36) of the cases,which was significantly lower in frequencyas compared to that in healthy controls(33.3%, 11/33) (p<0.05).
In SSc patients with a duration of the diseaseless than 3 years (mean duration 1.8±0.9years, range of 0.75-3), an early phase scle-roderma type capillaroscopic pattern wasfound in 50% of the cases (5/10). It is char-acterized by the presence of dilated capillar-ies, single giant capillaries, and single hem-orrhages, without capillary loss and with rel-atively preserved distribution as mentionedabove (Figure 1). In the other 50% (5/10) ofthe patients from this group an active phasescleroderma pattern was observed (Figure 2).In the group of SSc patients with a durationof the disease of more than 3 years (meanduration 12.4±6.7 years, range of 5-27), alate phase scleroderma capillaroscopic pat-tern was observed in 26.9% (7/26) of thepatients, characterized by the presence ofextensive, “desert-like” avascular areas andneoangiogenic capillaries (Figure 3). In61.5% (16/26) of the patients an active phasescleroderma type capillaroscopic pattern wasfound and an “early” phase pattern wasfound in 7.7% (2/26) of them. In 3.8% (1/26)of them, the images were not evaluatedbecause of poor visualization.
Digital ulcers at the hands were present in36.1% (13/36) of the SSc patients. In all of13 patients with digital ulcers (13/13), anactive phase scleroderma pattern wasobserved, which was characterized by thepresence of frequent giant capillaries, hem-orrhages, and avascular areas (Figure 4). Anactive phase scleroderma pattern was foundin 47.2% (17/36) of patients without digitalulcers.
Figure 3. Scleroderma type capillaroscopic pattern, a late phase. AA,avascular areas; N, neoangiogenesis.
Figure 4. Scleroderma type capillaroscopic pattern, an active phaseof the finger with active digital ulcer. G, giant capillaries; H, hemor-rhages; PO, pericapillary edema.
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Capillaroscopic findings in Systemic Sclerosis
Discussion
We have observed the classic scleroderma type capil-laroscopic pattern of the hands in SSc patients in 97.2%(35/36) of the cases, which is a confirmatory findingfor the high frequency of the specific capillaroscopicchanges in SSc. In SSc patients with a duration of thedisease less than 3 years, an early phase sclerodermacapillaroscopic pattern was found in 50% of the cases(5/10). In the group of SSc patients with a duration ofthe disease more than 3 years, a late phase capillaro-scopic pattern was found, while the frequency of earlyphase capillaroscopic pattern in this group was only7.7% (2/26). These results also confirm that capillaro-scopic changes in SSc differ in different phases of thedisease, although the duration of the disease is not theonly determining factor for their development. Theactivity of the disease and the level of different angio-genic and angiostatic factors play different and still notclearly defined roles for the dynamics of capillaroscop-ic changes in the different phases of SSc.
A significant association between the presence of digi-tal ulcers and the lower number of capillaries in the dis-tal row, as well as with a higher number of megacapil-laries and a higher loop diameter, was observed(Seibold et al., 1994). It has been speculated that thedevelopment of ulcerations in SSc may be associatedwith the presence of avascular areas at the capillaro-scopic examination (Sebastiani et al., 2009).
Conclusion
The results of the current study show that the presenceof digital ulcers at the hands of SSc patients is stronglyassociated with an active phase scleroderma type capil-laroscopic pattern. The observation of an active phasescleroderma type pattern in patients without digitalulcers may therefore be used in the future as a predic-tor for the development of trophic changes, an indica-tor for modulation of vasoactive treatment for the pre-vention of the development of digital ulcers, and as anadditional method for objective evaluation of the dis-ease activity score in SSc. An extensive evaluation withregular capillaroscopic examinations, 3-4 times peryear, may detect the dynamics in morphology of nail-fold capillaries during the course of the disease, andmay identify the time frame between the appearance ofan active phase capillaroscopic pattern and the devel-opment of digital ulcers.
Acknowledgment
The study was supported by an EULAR stipend to Dr.S. Lambova.
Disclosure
The authors report no conflicts of interest.
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