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ARTHRITIS & RHEUMATISM

Vol. 58, No. 2, February 2008, pp 571576


DOI 10.1002/art.23299
2008, American College of Rheumatology

Persistent Association of Nailfold Capillaroscopy Changes and


Skin Involvement Over Thirty-Six Months With Duration of
Untreated Disease in Patients With Juvenile Dermatomyositis
Stephanie Christen-Zaech,1 Roopa Seshadri,2 Joyce Sundberg,2 Amy S. Paller,1
and Lauren M. Pachman2
muscle DAS (P 0.025) were associated with a unicyclic
disease course.
Conclusion. Early treatment of juvenile DM may
lead to a unicyclic disease course. The non-unicyclic
disease course usually involves continuing skin manifestations with persistent nailfold capillaroscopy
changes. The correlation of nailfold capillaroscopy results with cutaneous but not with musculoskeletal signs
of juvenile DM over a 36-month period suggests that the
cutaneous and muscle vasculopathies have different
pathophysiologic mechanisms. These findings indicate
that efforts to identify the optimal treatment of cutaneous features in juvenile DM require greater attention.

Objective. To determine the association of


changes on nailfold capillaroscopy with clinical findings
and genotype in children with juvenile dermatomyositis
(DM), in order to identify potential differences in
disease course over 36 months.
Methods. At diagnosis of juvenile DM in 61
children prior to the initiation of treatment, tumor
necrosis factor (TNF) 308 allele and DQA1*0501
status was determined, juvenile DM Disease Activity
Scores (DAS) were obtained, and nailfold capillaroscopy was performed. The disease course was monitored
for 36 months. Variations within and between patients
were assessed by regression analysis.
Results. At diagnosis, shorter duration of untreated disease (P 0.05) and a lower juvenile DM skin
DAS (P 0.035) were associated with a unicyclic
disease course. Over 36 months, end-row loop (ERL)
regeneration was associated with lower skin DAS (P <
0.001) but not muscle DAS (P 0.98); ERL regeneration and decreased bushy loops were associated with a
shorter duration of untreated disease (P 0.04 for
both). At 36 months, increased ERL regeneration (P
0.007) and improvement of skin DAS (P < 0.001) and

Juvenile dermatomyositis (DM) is a systemic


inflammatory microvasculopathy that primarily affects
skin and muscle. The pathogenesis of juvenile DM
involves an immune-mediated process triggered by environmental factors in a genetically susceptible host.
Although evidence of an antecedent illness in the 34
months before onset of juvenile DM and strong expression of interferon-/induced genes in muscle of untreated children with juvenile DM (1) have suggested a
possible microbial trigger (2), polymerase chain reaction
studies of affected muscle failed to identify bacterial or
viral genomic material (3). HLADQA1*0501 and other
HLA markers (DQA1*301 and DRB*0301) appear to
be major risk factors for the development of juvenile
DM, but do not predict disease chronicity (4). In patients with untreated juvenile DM, increased synthesis of
tumor necrosis factor (TNF), a proinflammatory
cytokine, is common, and TNF 308A polymorphism
has been associated with a prolonged disease course,
pathologic calcifications (5), increased thrombospondin
1 production, and small vessel occlusion (6).
In juvenile DM, systemic immunosuppressive

Dr. Pachmans work was supported by the National Institute


of Arthritis and Musculoskeletal and Skin Diseases, NIH (grant
1-R0-1-AR-48289), the National Arthritis Foundation, and Cure JM.
1
Stephanie Christen-Zaech, MD, MSCI, Amy S. Paller, MD:
Northwestern University Feinberg School of Medicine, Chicago, Illi2
nois; Roopa Seshadri, PhD, AM, Joyce Sundberg, RN, Lauren M.
Pachman, MD: Northwestern University Feinberg School of Medicine
and Childrens Memorial Medical Center, Chicago, Illinois.
Dr. Pachman has received speaking fees (less than $10,000)
from Abbott.
Address correspondence and reprint requests to Lauren M.
Pachman, MD, Childrens Medical Research Center, Box 212, 2300
Childrens Plaza, Chicago, IL 60614. E-mail: pachman@
northwestern.edu.
Submitted for publication November 2, 2006; accepted in
revised form October 12, 2007.
571

572

CHRISTEN-ZAECH ET AL

therapy is guided by clinical findings, especially those


reflecting muscle disease, as well as laboratory results.
Recent analysis showed that serum levels of creatinephosphokinase, aldolase, lactate dehydrogenase, and
serum glutamic oxaloacetic transaminase sometimes fall
within the normal range in untreated children who have
had juvenile DM symptoms for 4 months, despite the
fact that they had clinical evidence of active cutaneous
and muscle inflammation as well as persistent immunologic abnormalities (7). More sensitive indicators of
disease activity are needed to help predict disease course
and guide therapy.
Periungual telangiectasia is a characteristic feature of juvenile DM. Nailfold capillaroscopy is a noninvasive technique that provides quantitative information
about capillary end-row loop (ERL) loss, areas of avascularity, and formation of bushy loops (BLs) (capillary
dilatations and branching arboreal capillary loops) (8).
In children with untreated juvenile DM, these features
reflect ongoing juvenile DM disease activity in the skin,
but not muscle, suggesting distinct pathophysiologic
mechanisms in skin versus muscle (9). To extend this
observation, we conducted a retrospective observational
study over 36 months, of children with newly diagnosed,
initially untreated juvenile DM. The main goal of this
study was to determine the association of nailfold capillaroscopy changes with demographic features (sex,
race, and age at disease onset), duration of untreated
disease; disease activity in skin and muscle, TNF 308
and HLADQA1*0501 alleles, and disease course. Additionally, these variables were used to assess possible
predictors of the disease course at the time of diagnosis
and to determine differences in disease course over 36
months.
PATIENTS AND METHODS
Patients. Untreated children with definite juvenile DM
(10), seen in the immunology/rheumatology clinic at Childrens
Memorial Medical Center between 1994 and 2004, were
enrolled in the study after informed consent was obtained from
their legal guardians. Patients were excluded if they had 2
nailfold capillaroscopy studies or juvenile DM Disease Activity
Score (DAS) assessments (11) in 36 months, prior treatment,
or a diagnosis of overlap syndrome. Study participants were
classified according to sex, race (white versus nonwhite), age at
disease onset, duration of untreated disease, disease course,
and TNF 308 and HLADQA1*0501 allele status. Data on
age at the time the first symptom of juvenile DM (rash or
muscle weakness) was recognized, and on the time between
onset of juvenile DM and the first administration of systemic
immunosuppressive therapy (7), were recorded.

Nailfold capillaroscopy and DAS assessments. Nailfold capillaroscopy, skin DAS, and muscle DAS assessments
were administered at the first diagnostic outpatient visit (baseline) and every 6 (3) months during a maximum of 36 (6)
months of followup. Nailfold capillaroscopy results and DAS
findings were each graded by the same individuals for each
patient at each time point, without knowledge of the results of
the other assessments. Nailfold capillaroscopy analyses were
performed as previously described (9). The nailfold capillaroscopy images were analyzed for the number of BLs and the total
number of loops (ERLs) per 3-mm section over 8 digits. The
severity of juvenile DM involvement was assessed using the
validated juvenile DM DAS (11). The total DAS (see Appendix A, available on the Arthritis & Rheumatism Web site at
http://www.mrw.interscience.wiley.com/suppmat/0004-3591/
suppmat/) is a 20-point scale with 2 subscales, one for musculoskeletal findings (assessing muscle function and extent of
weakness, with a maximum possible score of 11) and the other
for dermatologic findings (assessing the extent and severity of
rash, presence of Gottrons papules, and/or telangiectasia
[defined as tiny, superficial dilated blood vessels with no
particular pattern] of nailfolds, palate, and/or eyelids, with a
maximum possible score of 9). A higher DAS represents
greater disease activity. Nailfold capillaroscopy was also performed on 33 healthy children as controls, after informed
consent was obtained from legal guardians.
Genotyping. TNF 308 polymorphisms were identified as TNF 308A (AA/AG) or TNF 308G (GG).
HLADQA1*0501 status was determined as previously described (1).
Classification of disease course. Disease course was
classified as unicyclic or non-unicyclic. Unicyclic course was
defined as stable clinical status, with a total DAS remaining at
3 at all assessments during the 36-month observation period.
Our clinical experience suggests that a total DAS of 3 is
associated with clinically inactive, stable disease. Non-unicyclic
course was defined as a disease course showing evidence of
continued clinical activity, with a DAS of 3. In order to verify
the consistency of the definition of unicyclic and non-unicyclic
disease course, a subset of patients was classified based on
5-year followup data. The disease course classification using
3-year and 5-year data was then compared. In the unicyclic
disease course group, most of the children had discontinued all
immunosuppressive therapy before 36 months and had no
recurrence in the 23 years after discontinuation. Those in the
non-unicyclic disease course group were observed to have
disease activity necessitating either continuous or repeated
immunosuppressive therapy for 36 months. This report does
not focus on the type of therapy received by the children (dose,
route, or frequency) since the goal of the study was to identify
the association of the type of disease course with periungual
telangiectasia, regardless of the treatment utilized.
Statistical analysis. Values obtained in children with
untreated juvenile DM were compared with those obtained
after up to 36 months of therapy. Continuous changes were
analyzed using the values collected every 6 months (3
months) for up to 36 months. Repeated-measures linear
regression analysis was used to determine the association
between the primary predictor (DAS) and nailfold capillaroscopy outcomes. Time in the longitudinal model was treated as
a continuous variable. A mixed-effects approach was used to

NAILFOLD CAPILLAROSCOPY RESULTS AND SKIN INVOLVEMENT IN JUVENILE DM

Table 1. Demographic and clinical characteristics of the 61 children


with juvenile dermatomyositis*
Sex
Male
Female
Race
White
Nonwhite
TNF 308 promoter gene
AA/GA
GG
DQA1*0501 allele
Negative
Positive
Disease course over 36 months
Non-unicyclic
Unicyclic

12 (20)
49 (80)
49 (80)
12 (20)
20 (33)
41 (67)
30 (50)
30 (50)
36 (59)
25 (41)

* Values are the number (%). TNF tumor necrosis factor .


Not tested in 1 patient.

model intra- and interpatient variation. The primary focus of


the analyses was interpatient comparisons; intrapatient variability was included to account for the correlations between
the longitudinal observations in individual patients. Other
covariates considered were sex, race, age at disease onset,
duration of untreated disease, disease course, and TNF 308
and HLADQA1*0501 status. Association of baseline nailfold
capillaroscopy and DAS results with disease course was explored one predictor at time, using linear regression models
and controlling for the duration of untreated disease. Data are
presented as the mean SD. Data were analyzed using SAS
version 9.1. P values less than 0.05 were considered significant.

573

RESULTS
Patient characteristics. Over a 10-year period, 96
children were diagnosed as having untreated juvenile
DM by one of the authors (LMP). Of these, 19 had
received immunosuppressive therapy before their first
nailfold capillaroscopy, 7 had no TNF allele analysis, 2
had overlap syndrome, and 7 had only 1 followup visit.
The remaining 61 patients were included in the study.
The mean SD followup time was 29.6 10.2 months
(range 3.238.6). There were a total of 375 concurrent
nailfold capillaroscopy and DAS observations during the
36-month observation period. Forty-nine patients (80%)
had 5 observations. Followup data were available on
40 patients at 36 months and on 31 patients at 60 months.
Sex, race, disease course, and TNF 308 and HLA
DQA1*0501 allele status are summarized in Table 1.
Disease activity and nailfold capillaroscopy results. At baseline, the 61 patients had a mean SD of
5.63 1.70 ERLs/mm (range 3.1310.29) and 0.13
0.15 BLs/mm (range 00.71), a skin DAS of 5.59 1.45
(range 08), and a muscle DAS of 5.20 2.92 (range
010). At 36 months (n 40), the number of ERLs/mm
was 6.32 1.35 (range 3.139.33), the number of
BLs/mm was 0.15 0.16 (range 071), the skin DAS was
2.63 2.35 (range 07), and the muscle DAS was 0.56
0.88 (range 03). The 25th quartile and 75th quartile
values of the number of ERLs/mm in the 33 healthy
controls were 7.61/mm and 8.94/mm, respectively.

Table 2. Differences in disease features between juvenile DM patients with a unicyclic disease course and those with a non-unicyclic disease
course*

Duration of untreated disease, months


Age at disease onset, years
Nailfold capillaroscopy and DAS findings at baseline
ERLs, per mm
BLs, per mm
Skin DAS
Muscle DAS
Nailfold capillaroscopy and DAS findings after 36 months
of immunosuppressive treatment
ERLs, per mm
BLs, per mm
Skin DAS
Muscle DAS

Unicyclic disease course


(n 25 at baseline;
n 17 after 36 months
of treatment)

Non-unicyclic disease
course (n 36 at baseline;
n 23 after 36 months
of treatment)

6.92 6.11 (0.2620.80)


5.53 2.73 (1.5111.61)

15.61 24.64 (0.69111.01)


6.21 4.04 (1.0915.25)

0.05
0.44

5.96 1.74 (3.59.17)


0.11 0.13 (00.46)
5.12 1.48 (07)
5.0 2.94 (010)

5.32 1.62 (3.1310.29)


0.14 0.17 (00.71)
5.92 1.36 (38)
5.35 2.93 (010)

0.14
0.78
0.035
0.65

7.22 0.95 (5.819.33)


0.12 0.12 (00.33)
0.65 0.79 (02)
0.24 0.44 (01)

5.65 1.22 (3.139.04)


0.18 0.17 (00.71)
4.09 2.02 (07)
0.80 1.04 (03)

0.007
0.53
0.001
0.025

* Values are the mean SD (range). DM dermatomyositis; DAS juvenile DM Disease Activity Score; ERLs end-row loops; BLs bushy
loops.

574

CHRISTEN-ZAECH ET AL

Figure 1. Differences in study parameters between juvenile dermatomyositis (DM) patients with a unicyclic and those with a non-unicyclic disease
course over 36 months of treatment. Patients were untreated at study initiation. A, Regeneration of end-row loops. Shaded area shows the 25th to
75th quartile values in 33 healthy control children. B, Juvenile DM skin Disease Activity Score (DAS). C, Juvenile DM muscle DAS. D, End-row
loop regeneration, skin DAS, and muscle DAS findings at 60-month followup compared with those at 36-month followup, showing relatively little
change between the 2 time points. Values are the mean SD.

Results of genotype analysis for TNF 308 and


HLADQA1*0501. TNF 308 genotype analysis revealed that 20 (32.8%) of the patients with juvenile DM
had the AA/GA allele and 41 (67.2%) had the GG
allele. Thirty patients (50%) were positive for the HLA
DQA1*0501 allele and 30 (50%) were negative for the
allele; DQA1*0501 analysis was not performed on 1
patient.
Disease course. The disease course was nonunicyclic in 36 patients (59%) and unicyclic in 25 (41%).
Among the 31 children on whom 5-year followup data
were available (mean SD 78 6 months), a majority
(81%) of those with a unicyclic disease course at 3 years
continued to be classified as having a unicyclic course at
5 years.
Potential baseline predictors of disease course.
Shorter duration of untreated disease (P 0.05) and
lower skin DAS at baseline (P 0.035) were signifi-

cantly associated with a unicyclic disease course (Table


2). Type of disease course was not significantly associated with sex (P 0.21), age at disease onset (P 0.44),
number of ERLs/mm (P 0.14), number of BLs/mm
(P 0.78), muscle DAS (P 0.65), TNF 308
polymorphism (P 0.11), or HLADQA1*0501 allele
(P 0.19).
Nailfold capillaroscopy changes over 36 months
and their associations. Longitudinal data analysis with
time as a continuous measure (using all nailfold capillaroscopy studies from baseline up to 36 months of
systemic therapy) showed that increased ERL regeneration and decreased BL numbers were associated with
shorter duration of untreated disease (both P 0.04).
ERL regeneration was associated with lower skin DAS
(P 0.001) but was not associated with muscle DAS
(P 0.98). There were no statistically significant associations of either ERL or BL changes with sex (P 0.33

NAILFOLD CAPILLAROSCOPY RESULTS AND SKIN INVOLVEMENT IN JUVENILE DM

and P 0.12, respectively), race (P 0.19 and P 0.14,


respectively), age at disease onset (P 0.46 and P
0.44, respectively), TNF 308 polymorphism (P 0.32
and P 0.78, respectively), or presence of HLA
DQA1*0501 (P 0.15 and P 0.93, respectively).
Differences between unicyclic and non-unicyclic
disease course over 36 months. Increased ERL regeneration (P 0.007) and improvement in the skin DAS
(P 0.001) and muscle DAS (P 0.025) were each
associated with a unicyclic disease course in children
with juvenile DM after the start of therapy (Figures
1AC and Table 2). Figure 1D shows a composite view
of ERL, skin DAS, and muscle DAS data at 36 months
(n 40) and 60 months (n 31), demonstrating a lack
of significant change between the 2 time points. There
was no association between BL changes and disease
course (P 0.53) (Table 2).
DISCUSSION
The analysis of 375 observations of nailfold capillaroscopy, muscle DAS, and skin DAS obtained from
61 initially untreated children with juvenile DM during a
36-month treatment period showed that ERL loss was
associated with the cutaneous but not the musculoskeletal signs of juvenile DM, suggesting that damage to skin
and damage to muscle may have distinct pathophysiologic mechanisms. A longer duration of untreated disease correlated with worsening of the nailfold capillaroscopy changes. These results are consistent with our
previous finding of correlations between ERL changes
and severity of the rash and duration of disease in newly
diagnosed, untreated children with juvenile DM (9).
Persistent rash is not merely a cosmetic challenge; it can
be associated with complications such as cutaneous
calcinosis and may represent persistent vasculopathy
which could lead to long-term complications if untreated. A decreased nailfold capillaroscopy score was
recently shown to correlate with gastrointestinal vasculopathy and decreased absorption of orally administered
corticosteroids (12). Our finding of a strong correlation
between nailfold capillaroscopy changes and chronic
cutaneous manifestations in both treated and untreated
patients with juvenile DM suggests that early and more
aggressive management should be considered, even in
the absence of muscular weakness.
The disease course in children with juvenile DM
has traditionally been classified as unicyclic, polycyclic,
or chronic continuous (13). Previous data (5) suggest,
and these new longitudinal nailfold capillaroscopy data
confirm, that a simpler classification of unicyclic and

575

non-unicyclic disease course may be more useful. Patients with a polycyclic and chronic continuous course
overlap in their clinical features, prognoses, and recommended medical interventions; therefore, in the present
study they were combined into 1 group, called nonunicyclic disease. The definition of a unicyclic disease
course as a total DAS of 3 at all assessments (2
assessments in all cases) during a 36-month period is
both novel and helpful. This definition is new and
empirical and differs from previous uses of the term, in
which patients were classified as having unicyclic disease
if they had 1 episode of juvenile DM symptoms with
permanent remission 2 years after diagnosis and therapy. Further studies are needed to validate this new
definition.
A longer duration of untreated disease was found
to be associated not only with persistent nailfold capillaroscopy abnormalities, but also with a non-unicyclic
disease course. Consistent with previous findings (14),
early, effective therapy was associated with a higher
likelihood of a unicyclic pattern. The inflammatory
disease process itself evolves, and duration of untreated
disease is a critical element in the pathophysiology of the
illness (7). Nailfold capillaroscopy data at diagnosis
cannot be used to predict the course of disease, but if the
vascular abnormalities persist, they provide another
sensitive parameter of chronic disease activity and damage and should prompt the clinician to consider continued and aggressive therapy. Since nailfold capillaroscopy
findings correlated with skin disease activity, the observation of nailfold capillaroscopy abnormalities in the
setting of subtle skin changes is often very useful,
providing insight into the disease process. Our results
indicate that neither TNF 308 nor DQA1*0501 is a
useful marker for predicting the chronicity of the disease
in treated juvenile DM patients, and neither was associated with nailfold capillary changes. Investigators at our
institution previously reported that the TNF 308A
polymorphism was associated with disease chronicity
(5). The present seemingly contradictory results likely
reflect the shift toward more aggressive early therapy at
our center, leading to a milder disease course with
significant reduction in the development of pathologic
calcifications.
In children with treated juvenile DM, a unicyclic
disease course was associated with increased ERL regeneration and improvement in both skin DAS and
muscle DAS at 36 months, which was maintained at 60
months in 81% of patients. The improvement of skin
signs was observed to be a very gradual process, in
parallel with the regeneration of capillary ERLs. The

576

CHRISTEN-ZAECH ET AL

muscle inflammation, in contrast, responded much more


quickly to systemic immunosuppressive treatment, with
a rapid decrease in the muscle DAS. We conclude that
the non-unicyclic disease course is, in general, a reflection of continuing skin involvement with persistent nailfold capillaroscopy changes, given that current medical
intervention results in rapidly reversing muscle disease
but not in rapid change in skin disease. Specific therapy
for the cutaneous inflammation in juvenile DM would
improve the outcome of this often chronic illness.
AUTHOR CONTRIBUTIONS
Dr. Pachman 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. Christen-Zaech, Paller, Pachman.
Acquisition of data. Sundberg, Pachman.
Analysis and interpretation of data. Christen-Zaech, Seshadri, Sundberg, Paller, Pachman.
Manuscript preparation. Christen-Zaech, Seshadri, Paller, Pachman.
Statistical analysis. Seshadri.

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