The Prognostic Value of Nailfold Capilla
Pediatric Dermatology Vol. 23 No. 5 437–442, 2006
The Prognostic Value of Nailfold Capillary
Changes for the Development of Connective
Tissue Disease in Children and Adolescents with
Primary Raynaud Phenomenon: A Follow-up
Study of 250 Patients
Slavica Pavlov-Dolijanovic´, M.D., M.Sc.,* Nemanja Damjanov, M.D., Ph.D.,* Predrag Ostojic´,
M.D., M.Sc.,* Gordana Susˇic´, M.D., M.Sc.,* Roksanda Stojanovic´, M.D., Ph.D.,* Dragica
Gacic´, M.D.,* and Aleksandra Grdinic´, M.D., M.Sc.
*Institute of Rheumatology-Belgrade, KBC ‘‘Dragisˇa Misˇovic´-Dedinje’’, Belgrade, Serbia and Montenegro
Abstract: To assess the prognostic value of capillaroscopy findings for
the development of connective tissue disease in children and adolescents
with Raynaud phenomenon, we followed up a group of 250 (mean age
15 years) for 1 to 6 years after the first capillaroscopy was performed. Every
6 months they were screened for signs and symptoms of connective tissue
disease. Analysis was performed on capillary changes registered 6 months
before the development of connective tissue disease. Capillary changes
were classified into three types: normal, nonspecific, and sclerodermatous.
At the end of the follow-up period, 191 (76%) subjects had primary Raynaud
phenomenon, 27 (10.8%) were diagnosed as having undifferentiated connective tissue disease, and 32 (12.8%) fulfilled the criteria for a diagnosis of a
specific connective tissue disease. Systemic lupus erythematosus was
found in nine (3.6%) patients, rheumatoid arthritis in 10 (4%) patients (six of
them with juvenile onset rheumatoid arthritis), and scleroderma spectrum
disorders in 13 (5.2%). The mean time for the evolution of Raynaud phenomenon into undifferentiated connective tissue disease or a form of the
disease was 2 years. Most of the subjects with primary Raynaud phenomenon (173/191, 91%), undifferentiated connective tissue disease (22/27, 81%),
juvenile onset rheumatoid arthritis/rheumatoid arthritis (7/10, 70%), and
systemic lupus erythematosus (6/9, 67%) had normal capillary findings.
Nonspecific capillary changes occurred in 3 of 10 (30%) patients with rheumatoid arthritis, 2 of 9 (22%) with systemic lupus erythematosus, 4 of 27
(15%) with undifferentiated connective tissue disease, and 18 of 191 (9%)
with primary Raynaud phenomenon. Of all the subjects, only 10 (4%) showed
sclerodermatous disease type capillary changes 6 months before the
Address Correspondence to Slavica Pavlov-Dolijanovic´, M.D.,
M.Sc., Institute of Rheumatology-Belgrade, Institute of Rheumatology-Belgrade, Resavska 69, 11 000 Belgrade, Serbia and
Montenegro, or e-mail: dolijan@agrifaculty.bg.ac.yu or
dolijan@eunet.yu
2006 The Authors. Journal compilation 2006 Blackwell Publishing, Inc.
437
438 Pediatric Dermatology Vol. 23 No. 5 September ⁄ October 2006
expression of a particular disease: eight (62%) of these developed scleroderma spectrum disorders, one expressed systemic lupus erythematosus,
and one had undifferentiated connective tissue disease. We concluded that
there were no specific capillary changes predictive for future development of
systemic lupus erythematosus, juvenile onset rheumatoid arthritis/rheumatoid arthritis, and undifferentiated connective tissue disease in children and
adolescents with Raynaud phenomenon. Most of our study subjects with
Raynaud phenomenon who developed these diseases had normal capillary
findings or nonspecific changes. Children and adolescents who developed
scleroderma spectrum disorders showed a sclerodermatous type of capillary
changes 6 months before the expression of the disease, indicating that this
type of capillary changes in children and adolescents with Raynaud phenomenon highly correlated with further development of scleroderma spectrum disorders.
Raynaud phenomenon (RP) in adults, as well as in
children, is a vasospastic disorder characterized by the
episodic color changes of blanching, cyanosis, and
hyperemia of the digits in response to cold (1). In adults
RP can occur in response to emotional stress. However,
no evidence of relationship between the occurrence of RP
and emotional stress was found in children (2). It can be
classified as a primary phenomenon of unknown cause,
or secondary to a number of different diseases, such as
connective tissue diseases (CTD) (3). Most of the followup studies of children with RP noted the development of
associated CTD in 25% to 30% of those affected (4,5),
but some investigators reported up to 52% transition to
CTD and 15% transition to probable CTD (6). The
mean time between the onset of RP and development of
CTD in children was 2 to 6 years (4–6).
Early detection of CTD in subjects with RP is
important, and sometimes crucial for better treatment
results, and a better prognosis. Therefore, it is important
to assess the prognostic significance of various diagnostic
methods for early detection of CTD in subjects with RP.
One of these methods is nailfold capillaroscopy. This
simple, noninvasive, easy-to-perform method is very
important as a screening tool for detecting the subjects
with RP who are at high risk for the development of CTD
as adults (7). However, long-term protocol studies dealing with nailfold capillaroscopy changes in large
homogeneous groups of children and adolescents with
long-standing primary and secondary RP have not been
conducted.
Significant changes in capillary morphology are present in 80% of adult patients with scleroderma and
related disorders (7,8). These are called scleroderma (SD)
type capillary changes and include mainly a decrease in
capillary density and widened, giant loops, often surrounded by avascular areas. The extent of microangiopathy detected by nailfold capillaroscopy has been
shown to correlate with disease severity and prognosis
(7,9). Furthermore, the presence of SD type capillary
changes in adult patients with RP is thought to be
indicative of the future development of CTD, even in the
absence of other disease symptoms (10,11). Comparable
quantitative capillaroscopic data for healthy children, as
well as for pediatric rheumatology patients are limited
(12–15). Nevertheless, nailfold capillaroscopy findings
have been proposed as a potential marker for more
persistent disease in children with juvenile dermatomyositis (12) or systemic sclerosis (16). Correlation between
the degree of vaculopathy and the clinical course has also
been documented (12,13,16).
The aim of this study was to assess the prognostic
value of capillaroscopic findings for the development of
CTD in children and adolescents with RP, to detect the
spectrum of CTD associated with RP, and to evaluate
differences in duration of RP before the development of a
specific CTD in the same patient population.
PATIENTS AND METHODS
Patients
Two hundred fifty children and adolescents with RP (205
girls and 45 boys) aged 10 to 20 years (mean age 15 years)
were prospectively followed up in a study approved by
the Research Ethic Committee of the Institute of
Rheumatology, Belgrade. The median duration of RP
was 2 years, ranging from 1 month to 11 years.
Methods
Children and adolescents with RP were followed up for 1
to 6 years after the first capillaroscopy was done.
Capillaroscopy and a clinical search for criteria of CTD
were repeated every 6 months.
Nailfold capillaroscopy was carried out using the
semiquantitative methodology described by Damjanov
439
Pavlov-Dolijanovic´ et al: Nailfold Changes in Primary Raynaud Phenomenon
et al (17), which is similar to the technique described by
Maricq (18). Briefly, an OPTON microscope with 16·
and 100· magnifications was used. Cold light was provided by a Schott Mainz KL 150 fiber optic light source
(50/60Hz, 2000W, lampe 15V/150W, Germany). Each
subject was seated indoors for a minimum of 15 to
20 minutes before the examination, at a room temperature of 20 to 22C. The nailfolds of eight fingers (the
second, third, fourth, and fifth on both hands) were
examined in each patient, after a drop of immersion oil
was placed on the nailfold bed to improve resolution.
Fingers affected by recent local trauma were not analyzed. Capillary changes found 6 months before the criteria for a diagnosis of CTD were fulfilled were used for
analysis. These were classified into three types (7,8):
normal (typical hair pin structure), nonspecific capillary
changes (meandering and crossed capillaries, focal distribution of capillary hemorrhages, capillary thinning,
and capillary spasm), and the sclerodermatous type
mentioned above.
Clinical search comprised history taking, physical
examination, laboratory testing [including serologic tests
for antinuclear antibodies (ANA), rheumatoid factor,
and antiphospholipid (APL) antibodies], and particular
analyses (including radiographies and ultrasound). Serology and specific analyses were ordered according to
clinical impression. None of the patients used betablockers.
Statistical Analysis
Chi-squared test with Yate’s correction for continuity
was used. P values were calculated by two-sided Fisher’s
exact test.
percent of the subjects were female children, the female:male ratio was 5:1.
Follow-up Data
At the end of the follow-up period, 191 (76%) patients
with RP had no signs and symptoms of CTD, and they
were considered to have primary RP. Fifty-nine patients
(23.6%) developed CTD, and were considered to have
secondary RP (Table 2).
Distribution of the Types of Capillary Changes
Two hundred eleven children and adolescents with RP
(84.4%) were classified as having normal type, 29
(11.6%) patients were classified as having nonspecific
capillary changes, and 10 (4%) patients had the SD type
(Table 2). The frequency of normal capillary findings in
the subjects with primary RP was significantly higher
than that in the patients with secondary RP (p < 0.01).
On the other hand, the SD type was noted only among
the patients who had secondary RP. Nonspecific capillary changes had a similar distribution in both primary
and secondary RP subgroups.
Distribution of Subjects Who Developed CTD
After 2 years of follow-up, 27 of 250 (10.8%) subjects
had some signs and symptoms of CTD, but did not fulfill
the criteria for CTD, and they were considered to have
undifferentiated CTD (Table 3). Thirty-two (12.8%) of
TABLE 2. Distribution of the Types of Capillary Changes in
Children and Adolescents with Primary and Secondary Raynaud
Phenomenon (RP)
Type of capillary changes (patient
numbers)
RESULTS
Among 250 subjects included in the study, there were 110
(44%) children between 10 and 16 years of age, and 140
(56%) adolescents aged 17 to 20 years. Characteristics of
the study population are shown in Table 1. Eighty-two
Diagnosis
Normal
Nonspecific
SD type
Total
Primary RP
Secondary RP
Total
173
38
211
18
11
29
0
10
10
191
59
250
TABLE 1. Characteristics of the Study Population
No. of subjects
Age range (years)
10
11–12
13–14
15–16
17–18
19–20
Gender
Boys
Girls
3
14
35
58
73
67
45
205
TABLE 3. Distribution of Patients who Developed Connective
Tissue Diseases (CTD) during the 1- to 6-year Follow-up Period,
and Duration of RP before Diagnosis of CTD
Diagnosis
Number of
patients
Duration of RP before diagnosis of
CTD (years), mean (range)
UCTD
SLE
JRA/RA
SSD
Total
27
9
10
13
59
2.1
2.1
2.7
2.4
2.4
(8
(1
(1
(2
(1
mos–8 yrs)
mos–11 yrs)
mos–11 yrs)
mos–6 yrs)
mos–11 yrs)
440 Pediatric Dermatology Vol. 23 No. 5 September ⁄ October 2006
TABLE 4. Distribution of Different Types of Capillary Changes
in Patients with UCTD and a Articular CTD
Type of capillary changes (no. of patients)
Diagnosis
Normal
Nonspecific
SD type
Total
UCTD
JRA/RA
SLE
SSD
Total
22
7
6
3
38
4
3
2
2
11
1
0
1
8
10
27
10
9
13
59
the 250 subjects fulfilled the criteria for the diagnosis of a
particular CTD. The mean time between the beginning of
RP until diagnosis of a particular CTD was 2.4 years.
Among 32 patients with criteria sufficient for diagnosis of
a particular CTD, nine (3.6%) patients had systemic
lupus erythematosus (SLE), 10 (4%) patients had rheumatoid arthritis (RA) [six of these were with juvenile
onset RA (JRA)], and 13 (5.2%) subjects had scleroderma spectrum disorders (five with dermatomyositis/
polymyositis, five with systemic sclerosis, and three with
sclerodermatomyositis). The average duration of RP
until diagnosis of CTD in patients who fulfilled the criteria for JRA/RA was not significantly longer than in
those with other CTD (p ¼ 0.8).
The distribution of different types of capillary changes
in patients who developed CTD is shown in Table 4.
Normal capillary findings were not significantly differently distributed among the patients with undifferentiated connective tissue disease (UCTD), JRA/RA, and
SLE. The frequency of normal capillary findings in the
patients with UCTD was significantly higher than in
those in the scleroderma spectrum disorders (SSD) subgroup (p ¼ 0.0013). Nonspecific capillary changes were
distributed equally in the different subgroups of RP. SDtype capillary changes were present in 8 of 13 (61.5%)
patients with SSD, in 1 of 9 (11.1%) patients with SLE,
and 1 of 27 (3.7%) patients with UCTD. No JRA/RA
patient showed any significant abnormality of capillary
morphology. Sclerodermatous type capillary changes
were significantly more frequent among the patients with
SSD than among those with SLE and UCTD
(p < 0.01).
Antiphospholipid antibodies were found in five children who had digital pits. Two of them were APL antibody-positive, while others were negative.
DISCUSSION
The results of our study are comparable with those of
other authors, indicating that RP in children and adolescents, as well as in adults principally affects females,
and in most cases, is not associated with the future
development of CTD (5). In our study, for both primary
and secondary RP, 82% of patients were female children.
Approximately 76% of children and adolescents did not
have any recognized underlying CTD (primary RP) and
24% of children and adolescents developed CTD (secondary RP). The proportion of secondary RP in our
study population was lower than that in other studies.
Bethhencourt et al (19) found secondary RP in 10 of 32
(31.2%) children, Nigrovic et al found it in 19 of 52
(36.5%), and Duffy et al reported it in 14 of 27 (52%)
children. One reason for these differences was probably
the fact that we investigated children and adolescents
together (up to 20 years of age), whereas the other
authors included subjects only up to 18 years of age.
Our study confirms that, in most patients, RP is not
associated with the future development of CTD, but in
one of four children or adolescents it could be the first
symptom of CTD, such as UCTD, SSD, JRA/RA, and
SLE.
We found that the average RP duration before the
development of CTD in children and adolescents was
2 years. The mean duration of RP till development of
JRA/RA showed tendency to be longer than that for
other CTD (p ¼ 0.88). We were not able to see any significant difference in RP duration before development of
any CTD.
In our study, the greatest number of children and
adolescents during the follow-up period developed
UCTD (approximately 11%) or scleroderma spectrum
disease (2% of patients had systemic sclerosis, 2% of
patients had dermatomyositis/polymyositis, and 1.2%
had sclerodermatomyositis), and a lesser number of
patients developed JRA/RA (4%) or SLE (3.6%). Similar to our results, Nigrovic et al noted mixed CTD in
1.9% patients, scleroderma in 1.9% patients, and myositis in 1.9% patients. These authors found arthritis in a
large number of patients (28.8%). Rheumatoid arthritis
is usually not reported as CTD underlying RP, i.e., secondary RP. The data indicate that RP is not rare in adult
patients with RA (20,21). Saraux et al (21) registered RP
in 17.2% (54/332) RA adult patients. This group had a
slightly higher prevalence of vasculitis than RA patients
without RP. Among adults with RP, Grassi et al (22)
found that 5% (38/781) of patients had RA. Cassidy
reported 7% of RP adult patients had RA (23). However,
JRA is thought to represent only 1% (23) or less than 1%
(24) of the causes of RP. In our study, 6 of 250 (2.5%)
children with RP developed JRA during 1 to 6 years of
follow-up. Two of them were ANA positive (systemic
onset JRA), and others were ANA negative (oligo- and
polyarticular JRA). The later group is still being followed
up as JRA could shift to other CTD (25,26).
Pavlov-Dolijanovic´ et al: Nailfold Changes in Primary Raynaud Phenomenon
An association of APL antibodies and RP is reported
in adults (27) and children (5). The potential pathogenic
mechanism for APL antibodies in RP is binding and
activating endothelium (28). Endothelial damage and/or
thrombosis in the digits might result. We investigated for
APL antibodies in five children who had digital pits. The
test was positive in two of them. All five patients finally
developed SLE. In the study by Nigrovic et al (5), of
children with secondary RP who were found to be APL
antibody-positive (7/23; 30%), the majority (6/7) had
SLE. They also reported a high prevalence of APL
antibodies in children with primary RP (18/50; 36%).
In our study, subjects with primary RP and most of
children and adolescents with RP who developed SLE,
JRA/RA, and UCTD had normal capillary finding or
nonspecific capillary changes. Only one subject who
developed SLE (1/10, i.e., 11%) and one subject who
developed UCTD (1/27, i.e., 3.7%) during the followup period had SD type capillary changes 6 months
before the full expression of the disease. On the other
hand, 8 of 13 (61%) children and adolescents who
developed SSD (systemic sclerosis, dermatomyositis
and sclerodermatomyositis) exhibited SD type capillary
changes 6 months before the full expression of the
disease.
In our 250 children and adolescents, we found that
SD-type capillary changes significantly correlated with
the future development of scleroderma spectrum disorders. This finding was similar to that reported by
Duffy et al. Also, Dolezalova et al found a strong
correlation between lower capillary density, enlarged
dilated capillary loops, abnormal capillaries, avascular
areas, and nailfold vascular disarrangement (SD-type
changes), and CTD (juvenile dermatomyositis, systemic
sclerosis, and Mixed CTD) in children. Spencer-Green
et al found SD-type capillary changes in 11 of 19 (58%)
children with dermatomyositis. In contrast, children
and adolescents with primary RP and most of the
subjects who developed SLE, JRA/RA, and UCTD
had normal capillary findings or nonspecific capillary
changes. We did not find any specific capillary changes
predictive for future development of SLE, JRA/RA,
and UCTD in children and adolescents with RP. These
findings were similar to those of other studies in children, as well as in adults (16,29,30). Scleroderma type
capillary changes in children and adolescents with RP
strongly suggest the development of scleroderma spectrum disorders in the near future. This finding gives us
a chance to define, among a large number of children
and adolescents with RP, a small subgroup with a high
risk of development of SSD. Early detection of patients
with SSD allows for an early start of proper treatment,
and probably for a better prognosis.
441
ACKNOWLEDGMENTS
We thank Dr Zorica Sˇporcˇic´ for helpful comments on the
manuscript.
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The Prognostic Value of Nailfold Capillary
Changes for the Development of Connective
Tissue Disease in Children and Adolescents with
Primary Raynaud Phenomenon: A Follow-up
Study of 250 Patients
Slavica Pavlov-Dolijanovic´, M.D., M.Sc.,* Nemanja Damjanov, M.D., Ph.D.,* Predrag Ostojic´,
M.D., M.Sc.,* Gordana Susˇic´, M.D., M.Sc.,* Roksanda Stojanovic´, M.D., Ph.D.,* Dragica
Gacic´, M.D.,* and Aleksandra Grdinic´, M.D., M.Sc.
*Institute of Rheumatology-Belgrade, KBC ‘‘Dragisˇa Misˇovic´-Dedinje’’, Belgrade, Serbia and Montenegro
Abstract: To assess the prognostic value of capillaroscopy findings for
the development of connective tissue disease in children and adolescents
with Raynaud phenomenon, we followed up a group of 250 (mean age
15 years) for 1 to 6 years after the first capillaroscopy was performed. Every
6 months they were screened for signs and symptoms of connective tissue
disease. Analysis was performed on capillary changes registered 6 months
before the development of connective tissue disease. Capillary changes
were classified into three types: normal, nonspecific, and sclerodermatous.
At the end of the follow-up period, 191 (76%) subjects had primary Raynaud
phenomenon, 27 (10.8%) were diagnosed as having undifferentiated connective tissue disease, and 32 (12.8%) fulfilled the criteria for a diagnosis of a
specific connective tissue disease. Systemic lupus erythematosus was
found in nine (3.6%) patients, rheumatoid arthritis in 10 (4%) patients (six of
them with juvenile onset rheumatoid arthritis), and scleroderma spectrum
disorders in 13 (5.2%). The mean time for the evolution of Raynaud phenomenon into undifferentiated connective tissue disease or a form of the
disease was 2 years. Most of the subjects with primary Raynaud phenomenon (173/191, 91%), undifferentiated connective tissue disease (22/27, 81%),
juvenile onset rheumatoid arthritis/rheumatoid arthritis (7/10, 70%), and
systemic lupus erythematosus (6/9, 67%) had normal capillary findings.
Nonspecific capillary changes occurred in 3 of 10 (30%) patients with rheumatoid arthritis, 2 of 9 (22%) with systemic lupus erythematosus, 4 of 27
(15%) with undifferentiated connective tissue disease, and 18 of 191 (9%)
with primary Raynaud phenomenon. Of all the subjects, only 10 (4%) showed
sclerodermatous disease type capillary changes 6 months before the
Address Correspondence to Slavica Pavlov-Dolijanovic´, M.D.,
M.Sc., Institute of Rheumatology-Belgrade, Institute of Rheumatology-Belgrade, Resavska 69, 11 000 Belgrade, Serbia and
Montenegro, or e-mail: dolijan@agrifaculty.bg.ac.yu or
dolijan@eunet.yu
2006 The Authors. Journal compilation 2006 Blackwell Publishing, Inc.
437
438 Pediatric Dermatology Vol. 23 No. 5 September ⁄ October 2006
expression of a particular disease: eight (62%) of these developed scleroderma spectrum disorders, one expressed systemic lupus erythematosus,
and one had undifferentiated connective tissue disease. We concluded that
there were no specific capillary changes predictive for future development of
systemic lupus erythematosus, juvenile onset rheumatoid arthritis/rheumatoid arthritis, and undifferentiated connective tissue disease in children and
adolescents with Raynaud phenomenon. Most of our study subjects with
Raynaud phenomenon who developed these diseases had normal capillary
findings or nonspecific changes. Children and adolescents who developed
scleroderma spectrum disorders showed a sclerodermatous type of capillary
changes 6 months before the expression of the disease, indicating that this
type of capillary changes in children and adolescents with Raynaud phenomenon highly correlated with further development of scleroderma spectrum disorders.
Raynaud phenomenon (RP) in adults, as well as in
children, is a vasospastic disorder characterized by the
episodic color changes of blanching, cyanosis, and
hyperemia of the digits in response to cold (1). In adults
RP can occur in response to emotional stress. However,
no evidence of relationship between the occurrence of RP
and emotional stress was found in children (2). It can be
classified as a primary phenomenon of unknown cause,
or secondary to a number of different diseases, such as
connective tissue diseases (CTD) (3). Most of the followup studies of children with RP noted the development of
associated CTD in 25% to 30% of those affected (4,5),
but some investigators reported up to 52% transition to
CTD and 15% transition to probable CTD (6). The
mean time between the onset of RP and development of
CTD in children was 2 to 6 years (4–6).
Early detection of CTD in subjects with RP is
important, and sometimes crucial for better treatment
results, and a better prognosis. Therefore, it is important
to assess the prognostic significance of various diagnostic
methods for early detection of CTD in subjects with RP.
One of these methods is nailfold capillaroscopy. This
simple, noninvasive, easy-to-perform method is very
important as a screening tool for detecting the subjects
with RP who are at high risk for the development of CTD
as adults (7). However, long-term protocol studies dealing with nailfold capillaroscopy changes in large
homogeneous groups of children and adolescents with
long-standing primary and secondary RP have not been
conducted.
Significant changes in capillary morphology are present in 80% of adult patients with scleroderma and
related disorders (7,8). These are called scleroderma (SD)
type capillary changes and include mainly a decrease in
capillary density and widened, giant loops, often surrounded by avascular areas. The extent of microangiopathy detected by nailfold capillaroscopy has been
shown to correlate with disease severity and prognosis
(7,9). Furthermore, the presence of SD type capillary
changes in adult patients with RP is thought to be
indicative of the future development of CTD, even in the
absence of other disease symptoms (10,11). Comparable
quantitative capillaroscopic data for healthy children, as
well as for pediatric rheumatology patients are limited
(12–15). Nevertheless, nailfold capillaroscopy findings
have been proposed as a potential marker for more
persistent disease in children with juvenile dermatomyositis (12) or systemic sclerosis (16). Correlation between
the degree of vaculopathy and the clinical course has also
been documented (12,13,16).
The aim of this study was to assess the prognostic
value of capillaroscopic findings for the development of
CTD in children and adolescents with RP, to detect the
spectrum of CTD associated with RP, and to evaluate
differences in duration of RP before the development of a
specific CTD in the same patient population.
PATIENTS AND METHODS
Patients
Two hundred fifty children and adolescents with RP (205
girls and 45 boys) aged 10 to 20 years (mean age 15 years)
were prospectively followed up in a study approved by
the Research Ethic Committee of the Institute of
Rheumatology, Belgrade. The median duration of RP
was 2 years, ranging from 1 month to 11 years.
Methods
Children and adolescents with RP were followed up for 1
to 6 years after the first capillaroscopy was done.
Capillaroscopy and a clinical search for criteria of CTD
were repeated every 6 months.
Nailfold capillaroscopy was carried out using the
semiquantitative methodology described by Damjanov
439
Pavlov-Dolijanovic´ et al: Nailfold Changes in Primary Raynaud Phenomenon
et al (17), which is similar to the technique described by
Maricq (18). Briefly, an OPTON microscope with 16·
and 100· magnifications was used. Cold light was provided by a Schott Mainz KL 150 fiber optic light source
(50/60Hz, 2000W, lampe 15V/150W, Germany). Each
subject was seated indoors for a minimum of 15 to
20 minutes before the examination, at a room temperature of 20 to 22C. The nailfolds of eight fingers (the
second, third, fourth, and fifth on both hands) were
examined in each patient, after a drop of immersion oil
was placed on the nailfold bed to improve resolution.
Fingers affected by recent local trauma were not analyzed. Capillary changes found 6 months before the criteria for a diagnosis of CTD were fulfilled were used for
analysis. These were classified into three types (7,8):
normal (typical hair pin structure), nonspecific capillary
changes (meandering and crossed capillaries, focal distribution of capillary hemorrhages, capillary thinning,
and capillary spasm), and the sclerodermatous type
mentioned above.
Clinical search comprised history taking, physical
examination, laboratory testing [including serologic tests
for antinuclear antibodies (ANA), rheumatoid factor,
and antiphospholipid (APL) antibodies], and particular
analyses (including radiographies and ultrasound). Serology and specific analyses were ordered according to
clinical impression. None of the patients used betablockers.
Statistical Analysis
Chi-squared test with Yate’s correction for continuity
was used. P values were calculated by two-sided Fisher’s
exact test.
percent of the subjects were female children, the female:male ratio was 5:1.
Follow-up Data
At the end of the follow-up period, 191 (76%) patients
with RP had no signs and symptoms of CTD, and they
were considered to have primary RP. Fifty-nine patients
(23.6%) developed CTD, and were considered to have
secondary RP (Table 2).
Distribution of the Types of Capillary Changes
Two hundred eleven children and adolescents with RP
(84.4%) were classified as having normal type, 29
(11.6%) patients were classified as having nonspecific
capillary changes, and 10 (4%) patients had the SD type
(Table 2). The frequency of normal capillary findings in
the subjects with primary RP was significantly higher
than that in the patients with secondary RP (p < 0.01).
On the other hand, the SD type was noted only among
the patients who had secondary RP. Nonspecific capillary changes had a similar distribution in both primary
and secondary RP subgroups.
Distribution of Subjects Who Developed CTD
After 2 years of follow-up, 27 of 250 (10.8%) subjects
had some signs and symptoms of CTD, but did not fulfill
the criteria for CTD, and they were considered to have
undifferentiated CTD (Table 3). Thirty-two (12.8%) of
TABLE 2. Distribution of the Types of Capillary Changes in
Children and Adolescents with Primary and Secondary Raynaud
Phenomenon (RP)
Type of capillary changes (patient
numbers)
RESULTS
Among 250 subjects included in the study, there were 110
(44%) children between 10 and 16 years of age, and 140
(56%) adolescents aged 17 to 20 years. Characteristics of
the study population are shown in Table 1. Eighty-two
Diagnosis
Normal
Nonspecific
SD type
Total
Primary RP
Secondary RP
Total
173
38
211
18
11
29
0
10
10
191
59
250
TABLE 1. Characteristics of the Study Population
No. of subjects
Age range (years)
10
11–12
13–14
15–16
17–18
19–20
Gender
Boys
Girls
3
14
35
58
73
67
45
205
TABLE 3. Distribution of Patients who Developed Connective
Tissue Diseases (CTD) during the 1- to 6-year Follow-up Period,
and Duration of RP before Diagnosis of CTD
Diagnosis
Number of
patients
Duration of RP before diagnosis of
CTD (years), mean (range)
UCTD
SLE
JRA/RA
SSD
Total
27
9
10
13
59
2.1
2.1
2.7
2.4
2.4
(8
(1
(1
(2
(1
mos–8 yrs)
mos–11 yrs)
mos–11 yrs)
mos–6 yrs)
mos–11 yrs)
440 Pediatric Dermatology Vol. 23 No. 5 September ⁄ October 2006
TABLE 4. Distribution of Different Types of Capillary Changes
in Patients with UCTD and a Articular CTD
Type of capillary changes (no. of patients)
Diagnosis
Normal
Nonspecific
SD type
Total
UCTD
JRA/RA
SLE
SSD
Total
22
7
6
3
38
4
3
2
2
11
1
0
1
8
10
27
10
9
13
59
the 250 subjects fulfilled the criteria for the diagnosis of a
particular CTD. The mean time between the beginning of
RP until diagnosis of a particular CTD was 2.4 years.
Among 32 patients with criteria sufficient for diagnosis of
a particular CTD, nine (3.6%) patients had systemic
lupus erythematosus (SLE), 10 (4%) patients had rheumatoid arthritis (RA) [six of these were with juvenile
onset RA (JRA)], and 13 (5.2%) subjects had scleroderma spectrum disorders (five with dermatomyositis/
polymyositis, five with systemic sclerosis, and three with
sclerodermatomyositis). The average duration of RP
until diagnosis of CTD in patients who fulfilled the criteria for JRA/RA was not significantly longer than in
those with other CTD (p ¼ 0.8).
The distribution of different types of capillary changes
in patients who developed CTD is shown in Table 4.
Normal capillary findings were not significantly differently distributed among the patients with undifferentiated connective tissue disease (UCTD), JRA/RA, and
SLE. The frequency of normal capillary findings in the
patients with UCTD was significantly higher than in
those in the scleroderma spectrum disorders (SSD) subgroup (p ¼ 0.0013). Nonspecific capillary changes were
distributed equally in the different subgroups of RP. SDtype capillary changes were present in 8 of 13 (61.5%)
patients with SSD, in 1 of 9 (11.1%) patients with SLE,
and 1 of 27 (3.7%) patients with UCTD. No JRA/RA
patient showed any significant abnormality of capillary
morphology. Sclerodermatous type capillary changes
were significantly more frequent among the patients with
SSD than among those with SLE and UCTD
(p < 0.01).
Antiphospholipid antibodies were found in five children who had digital pits. Two of them were APL antibody-positive, while others were negative.
DISCUSSION
The results of our study are comparable with those of
other authors, indicating that RP in children and adolescents, as well as in adults principally affects females,
and in most cases, is not associated with the future
development of CTD (5). In our study, for both primary
and secondary RP, 82% of patients were female children.
Approximately 76% of children and adolescents did not
have any recognized underlying CTD (primary RP) and
24% of children and adolescents developed CTD (secondary RP). The proportion of secondary RP in our
study population was lower than that in other studies.
Bethhencourt et al (19) found secondary RP in 10 of 32
(31.2%) children, Nigrovic et al found it in 19 of 52
(36.5%), and Duffy et al reported it in 14 of 27 (52%)
children. One reason for these differences was probably
the fact that we investigated children and adolescents
together (up to 20 years of age), whereas the other
authors included subjects only up to 18 years of age.
Our study confirms that, in most patients, RP is not
associated with the future development of CTD, but in
one of four children or adolescents it could be the first
symptom of CTD, such as UCTD, SSD, JRA/RA, and
SLE.
We found that the average RP duration before the
development of CTD in children and adolescents was
2 years. The mean duration of RP till development of
JRA/RA showed tendency to be longer than that for
other CTD (p ¼ 0.88). We were not able to see any significant difference in RP duration before development of
any CTD.
In our study, the greatest number of children and
adolescents during the follow-up period developed
UCTD (approximately 11%) or scleroderma spectrum
disease (2% of patients had systemic sclerosis, 2% of
patients had dermatomyositis/polymyositis, and 1.2%
had sclerodermatomyositis), and a lesser number of
patients developed JRA/RA (4%) or SLE (3.6%). Similar to our results, Nigrovic et al noted mixed CTD in
1.9% patients, scleroderma in 1.9% patients, and myositis in 1.9% patients. These authors found arthritis in a
large number of patients (28.8%). Rheumatoid arthritis
is usually not reported as CTD underlying RP, i.e., secondary RP. The data indicate that RP is not rare in adult
patients with RA (20,21). Saraux et al (21) registered RP
in 17.2% (54/332) RA adult patients. This group had a
slightly higher prevalence of vasculitis than RA patients
without RP. Among adults with RP, Grassi et al (22)
found that 5% (38/781) of patients had RA. Cassidy
reported 7% of RP adult patients had RA (23). However,
JRA is thought to represent only 1% (23) or less than 1%
(24) of the causes of RP. In our study, 6 of 250 (2.5%)
children with RP developed JRA during 1 to 6 years of
follow-up. Two of them were ANA positive (systemic
onset JRA), and others were ANA negative (oligo- and
polyarticular JRA). The later group is still being followed
up as JRA could shift to other CTD (25,26).
Pavlov-Dolijanovic´ et al: Nailfold Changes in Primary Raynaud Phenomenon
An association of APL antibodies and RP is reported
in adults (27) and children (5). The potential pathogenic
mechanism for APL antibodies in RP is binding and
activating endothelium (28). Endothelial damage and/or
thrombosis in the digits might result. We investigated for
APL antibodies in five children who had digital pits. The
test was positive in two of them. All five patients finally
developed SLE. In the study by Nigrovic et al (5), of
children with secondary RP who were found to be APL
antibody-positive (7/23; 30%), the majority (6/7) had
SLE. They also reported a high prevalence of APL
antibodies in children with primary RP (18/50; 36%).
In our study, subjects with primary RP and most of
children and adolescents with RP who developed SLE,
JRA/RA, and UCTD had normal capillary finding or
nonspecific capillary changes. Only one subject who
developed SLE (1/10, i.e., 11%) and one subject who
developed UCTD (1/27, i.e., 3.7%) during the followup period had SD type capillary changes 6 months
before the full expression of the disease. On the other
hand, 8 of 13 (61%) children and adolescents who
developed SSD (systemic sclerosis, dermatomyositis
and sclerodermatomyositis) exhibited SD type capillary
changes 6 months before the full expression of the
disease.
In our 250 children and adolescents, we found that
SD-type capillary changes significantly correlated with
the future development of scleroderma spectrum disorders. This finding was similar to that reported by
Duffy et al. Also, Dolezalova et al found a strong
correlation between lower capillary density, enlarged
dilated capillary loops, abnormal capillaries, avascular
areas, and nailfold vascular disarrangement (SD-type
changes), and CTD (juvenile dermatomyositis, systemic
sclerosis, and Mixed CTD) in children. Spencer-Green
et al found SD-type capillary changes in 11 of 19 (58%)
children with dermatomyositis. In contrast, children
and adolescents with primary RP and most of the
subjects who developed SLE, JRA/RA, and UCTD
had normal capillary findings or nonspecific capillary
changes. We did not find any specific capillary changes
predictive for future development of SLE, JRA/RA,
and UCTD in children and adolescents with RP. These
findings were similar to those of other studies in children, as well as in adults (16,29,30). Scleroderma type
capillary changes in children and adolescents with RP
strongly suggest the development of scleroderma spectrum disorders in the near future. This finding gives us
a chance to define, among a large number of children
and adolescents with RP, a small subgroup with a high
risk of development of SSD. Early detection of patients
with SSD allows for an early start of proper treatment,
and probably for a better prognosis.
441
ACKNOWLEDGMENTS
We thank Dr Zorica Sˇporcˇic´ for helpful comments on the
manuscript.
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