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Diagnostic potential of in vivo capillary microscopy in scleroderma and related disorders.

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183
DIAGNOSTIC POTENTIAL OF
IN VIVO CAPILLARY MICROSCOPY IN
SCLERODERMA AND RELATED DISORDERS
H. R. MARICQ, E. C. LeROY, W. A. D’ANGELO, T. A. MEDSGER, Jr., G. P. RODNAN,
G. C. SHARP, and J. F. WOLFE
The prevalence of scleroderma-type capillary abnormalities, as observed by in vivo microscopy, was determined in 173 patients from three rheumatic disease
centers. The patients had a variety of connective tissue
diseases: scleroderma (systemic sclerosis) 50; systemic
lupus erythematosus 60,mixed connective tissue disease
26; Raynaud’s disease 11; other rheumatic disorders 26.
Enlarged and deformed capillary loops surrounded by
relatively avascular areas, most prominently in the nailfolds, were found in 82%of patients with scleroderma
and in 54% with mixed connective tissue disease. The
rarity of these abnormalities in systemic lupus erythematosus (2%)despite the presence of Raynaud’s phenomenon suggests that they are not an expression of the
Raynaud’s phenomenon frequently associated with
scleroderma and mixed connective tissue disease. The
single patient with Raynaud’s disease and sclerodermatype capillary changes subsequently developed scleroderma.
Supported in part by grants from the National Institutes of
Health (AM20571), the State of South Carolina, the RGK Foundation, the Charlotte and Sidney Lifschultz Foundation, the South Carolina Chapter of the Arthritis Foundation, the Lupus Foundation,
and the National Institutes of Health Biomedical Research Grant
(RR05420) to the Medical University of South Carolina.
H. R. Maricq, MD: Medical University of South Carolina; E.
C. LeRoy, MD: Medical University of South Carolina; W. M.
D’Angelo, MD: State University of New York at Stony Brook; T. A.
Medsger, Jr., MD: University of Pittsburgh School of Medicine; G. P.
Rodnan, MD: University of Pittsburgh School of Medicine; G. C.
Sharp, MD: University of Missouri School of Medicine, Columbia; J.
F. Wolfe, MD: University of Missouri School of Medicine.
Address reprint requests to H. R. Maricq, MD, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South
Carolina 29403.
Submitted for publication August 15, 1979; accepted in revised form October 10, 1979.
Arthritis and Rheumatism, Vol. 23, No. 2 (February 1980)
Although the diagnosis of scleroderma (systemic
sclerosis) presents no problem once the full clinical picture of hidebound skin has developed, there is no single
symptom, sign, or laboratory test that is pathognomonic
in the early stages of the disease. An early diagnostic
test is needed to study pathogenetic mechanisms in incipient scleroderma before these become obscured by
the fibrotic process. Raynaud’s phenomenon and involvement of skin (scleroderma) usually precede clinically apparent visceral disease (systemic sclerosis) but,
unfortunately, the skin biopsy is generally of little or no
assistance in early diagnosis (1). Moreover, by the time
the most characteristic histopathologic changes are
found (e.g. in the kidney) the patient is already seriously
and often terminally ill (2). In previous studies utilizing
in vivo microscopy we have observed a characteristic
pattern of skin capillary abnormalities in 86% of patients with scleroderma (3,4).
The present study was designed to determine the
usefulness of skin capillary abnormalities in distinguishing scleroderma from other connective tissue diseases,
i.e. the specificity of “scleroderma pattern” capillary abnormalities previously described (5). To obtain a large
sample of patients with connective tissue disease in a
short period of time and to compare our earlier findings
on a cross-section of patients diagnosed by physicians
with various backgrounds and locales (with possibly different patient populations and diagnostic habits), a field
study was carried out.
MATERIALS AND METHODS
Subjects. One hundred seventy-three patients were
examined at the following Arthritis Centers: the University of
Pittsburgh, Pittsburgh, Pennsylvania (65), the Catholic Medi-
184
MARICQ ET AL
Table 1. Disease duration:
From first
symptoms
Median
Scleroderma
Systemic lupus
erythematosus
Mixed connective tissue
disease
Raynaud’s disease
Range
From diagnosis
Median
Range
9.2
0.8-36
4.3
0.1-23
8.5
1-40
5.5
0.2-39
5.7
4.3
0.6-17
1-32
3.5
1.0
0.1-8
0.417
In years.
cal Affiliation, Queens General Hospital, New York City,
(89), and the University of Missouri, Columbia, Missouri (19).
Patients were categorized according to the clinical diagnosis
provided by the center physicians, all experienced in their
field, without knowledge of the capillary studies. The following diagnostic groups were represented: 1) scleroderma: 50 patients; 45 women and 5 men, 2) systemic lupus erythematosus:
60 patients; 58 women and 2 men, 3) mixed connective tissue
disease: 26 patients; 24 women and 2 men, 4) Raynaud‘s disease: 11 patients; 10 women and 1 man, and 5) a variety of
other rheumatic diseases (26 patients including 8 with polymyositis, 2 with dermatomyositis, 2 with discoid lupus erythematosus, 2 with rheumatoid arthritis, 2 with ankylosing
spondylitis, 3 with scleroderma-polymyositis overlap, 2 with
systemic lupus erythematosus--mixed connective tissue disease
overlap, 3 with probable systemic lupus erythematosus, 1 with
possible scleroderma, and 1 with scleredema).
Only the results of patients in the first four groups
were used for statistical analysis (n = 147). The ages of these
patients were as follows: scleroderma: range 27-78, mean 52
years; systemic lupus erythematosus: range 17-64, mean 41
years; mixed connective tissue disease: range 17-55, mean 40
years; and Raynaud‘s disease: range 23-69, mean 42 years.
The disease duration is shown in Table 1.
Techniques. Observations and photography of skin
capillaries were performed by in vivo widefield capillaroscopic technique on all patients as previously described (6,7).
The following sites were examined: nailfold and dorsum of
the distal phalanx of at least 4 fingers, dorsum of the middle
phalanx, dorsum of the proximal interphalangeal joint and of
the fingerpad of at least 2 fingers. All capillary observations
were performed by the senior author (HRM) during the field
trips undertaken with technical support and portable equipment. A minimum of two photomicrographs was obtained
from each patient and coded for “blind” analysis.
Capillary pattern analysis was performed by the senior author (HRM), after the field trips, from coded observation notes and coded photographs; the results were then combined for final ratings of subjects. Our previous experience has
shown an excellent correlation (P < 0.0005) between results
based on direct observations and those based on coded photographic data on the same subjects rated “blindly” by an independent investigator (4).
This study was focused primarily on estimating the
prevalence of the scleroderma-pattern capillary abnormalities
which consist of enlarged and deformed capillary loops often
surrounded by relatively avascular areas especially visible in
the nailfold capillary bed. Figures 1 through 4 illustrate typical scleroderma-pattern abnormalities in the nailfold. In addition, other microvascular abnormalities were noted when encountered, i.e. patterns not seen in our previous experience
with over 800 healthy control subjects (8).
Figure 1. Nailfold capillaries in an average subject (normal pattern)
CAPILLARY MICROSCOPY IN SCLERODERMA
Figure 2. Large dilated capillaries at the edge of the nailfold (scleroderma pattern).
Figure 3. Dilated capillaries contrasting with adjacent avascular areas (scleroderma pattern).
185
MARICQ ET AL
186
Figure 4. Extensive loss of capillaries combined with dilatation of some capillary loops (scleroderma pattern).
RESULTS
Distribution of capillary pattern abnormalities.
The prevalence of scleroderma-pattern capillary abnormalities in the four diagnostic groups is shown in Figure
5. The number of patients with scleroderma pattern in
each group was as follows: scleroderma 41 (82%); systemic lupus erythematosus 1 (2%); mixed connective tissue disease 14 (54%); and Raynaud’s disease 1 (9%).
Three of the 26 patients with the rheumatic disorders
listed in the Materials and Methods section showed the
scleroderma-pattern capillary abnormalities. Their diagnoses were ( 1 each): dermatomyositis, polymyositis, and
the systemic lupus erythematosus-mixed connective tissue disease overlap.
Tortuous capillaries, some resembling the
“meandering” capillary loops described by Redisch et
a1 (9), were noted in 25 patients with systemic lupus erythematosus (42%), 3 patients with scleroderma (6%), 3
patients with mixed connective tissue disease (12%), and
4 patients with Raynaud’s disease (36%). Two additional patients with mixed connective tissue disease displayed both a scleroderma pattern and tortuous capillaries. (They were already included among the 14 with
scleroderma pattern reported above.) Nonspecific mi-
crovascular changes were present in 17 patients with
systemic lupus erythematosus (28%), 4 patients with
scleroderma (8%), 3 with mixed connective tissue disease (12%), and 2 with Raynaud’s disease (18%). Many
individuals with systemic lupus erythematosus (17,28%)
and Raynaud’s disease (4,36%) showed no capillary ab-
SD
MCTD
RD
SLE
Figure 5. Prevalence of scleroderma-pattern capillary abnormalities in
different diagnostic groups: scleroderma (SD), mixed connective tissue disease (MCTD), Raynaud‘s disease (RD), and systemic lupus
erythematosus (SLE).
CAPILLARY MICROSCOPY IN SCLERODERMA
8o
I
187
N=60
N=SO
SD
PATTERN
SPEC
CAP
ABN
Figure 6. Capillary observations in scleroderma. N O N SPEC = nonspecific; TORT CAP = tortuous capillaries; N O ABN = no abnormalities.
normalities, as did 6 patients with mixed connective tissue disease (23%) but only 2 with scleroderma (4%).
The distribution of different capillary patterns in
the several diagnostic groups is shown in Figures 6
through 8. This distribution is significantly different
from that expected by chance ($dfg = 87.67; P < 0.001).
Correlation of capillaroscopic findings with Raynaud’s phenomenon. The presence of Raynaud’s phenomenon was reported in 46 patients with scleroderma
(92%), 37 patients with systemic lupus erythematosus
(62%), and all patients with Raynaud’s disease and
mixed connective tissue disease. Only one systemic
lupus erythematosus patient with Raynaud’s phenomenon showed scleroderma-pattern capillary abnormalities.
Correlation of capillary observations and disease
activity. Information on disease activity was available
for a limited number of study patients with mixed con*O
Lu
L
N=26
t
t
PATTERN
NON
SPEC
TORT
CAP
NO
ABN
Figure 8. Capillary observations in systemic lupus erythematosus. S D
= scleroderma; NON SPEC = nonspecific; TORT CAP = tortuous
capillaries; N O ABN = no abnormalities.
nective tissue disease. Although a possible correlation
between active disease (greater number of organs involved, more scleroderma features, higher requirements
for corticosteroids and/or cyclophosphamide) and pronounced capillary abnormalities (combined with loss of
capillary loops) was suggested by the data, the small
number of cases did not allow reliable statistical analysis of this association.
A followup from one clinic revealed that the
single patient in the Raynaud’s disease group with
scleroderma-type capillary abnormalities was found to
have scleroderma 5 months after capillary examination.
Another patient with apparently mild mixed connective
tissue disease at the time she was studied was found to
have pronounced scleroderma-type capillary abnormalities. She died the following year with severe proliferative obliterative vascular disease involving particularly
the pulmonary and renal vasculature.
There was no correlation between the duration
of the disease (from first symptoms or from diagnosis)
and the scleroderma-pattern capillary abnormalities in
patients with scleroderma and mixed connective tissue
disease.
401-LL
DISCUSSION
20
SD
PATTERN
NON
SPEC
TORT
CAP
SD
TORT
NO
ABN
Figure 7. Capillary observations in mixed connective tissue disease.
S D = scleroderma; N O N SPEC = non specific; TORT CAP = tortuous capillaries; N O ABN = no abnormalities.
The results of this study confirm our earlier findings that a characteristic pattern of capillary abnormalities occurs in over 80% of patients with scleroderma (35). The same pattern is also seen in related disorders
such as Raynaud’s disease, mixed connective tissue disease, and dermatomyositis but rarely in systemic lupus
erythematosus (only 1 of 60 patients in this study). The
presence of this pattern in some Raynaud’s disease patients is not surprising, since a proportion of them even-
188
tually develop scleroderma. Thus, the scleroderma-type
capillary abnormalities may be of diagnostic or prognostic value in Prescleroderma RaYnaud’s syndrome:
i.e. in patients with Raynaud’s syndrome who are destined to develop scleroderma but who have not yet developed typical skin changes. This hypothesis is supported by the change in diagnosis of the Raynaud’s
disease patient with scleroderma-pattern capillary abnormalities and by our own experience with Raynaud‘s
disease patients (10).
Scleroderma-pattern capillary abnormalities
were present in about half the patients with mixed connective tissue disease; this half tended to have more active disease, more organ involvement, more scleroderma
features, and higher requirements for corticosteroids
and/or cyclophosphamide to control the disease than
those without scleroderma-pattern. Since followup reports of mixed connective tissue disease patients have
shown a number of patients whose subsequent manifestations are mainly those of scleroderma, it is probable
that the scleroderma-pattern capillary abnormalities indicate such a prognosis in this group of patients. The
proportion of scleroderma-pattern capillary abnormalities found in mixed connective tissue disease patients in
the present study is similar to the clinical impression at
5 years after the initial diagnosis of mixed connective
tissue disease (1 1,12).
In our earlier studies (3-6) most patients with
dermatomyositis had nailfold capillary findings indistinguishable from the scleroderma-pattern, an observation also noted in the present study (1 of 2 patients
with dermatomyositis showed such a change). A close
relationship between scleroderma and dermatomyositis
has been recognized for many years (13) and it is known
that distribution and morphology of the visceral vascular lesions are often strikingly similar in these disorders
(14).
Thus it appears that the scleroderma-pattern
capillary abnormalities may be characteristic of “scleroderma spectrum disorders,” including classic scleroderma, prescleroderma Raynaud’s disease, mixed connective tissue disease destined to become seleroderma,
and dermatomyositis which may share common pathogenetic mechanisms but have different clinical expressions due to other as yet undetermined factors.
At present the single specific indicator of scleroderma is (15,16) proximal skin involvement, a relatively
late feature; capillary microscopy is proposed as a
simple, practical procedure useful in early recognition
of this disease, and of prognostic value.
MARICQ ET AL
ACKNOWLEDGMENTS
The technical assistance of Joyce Hardin, Mary
Pennington, Maureen Pupillo, and Vasu Nair is hereby gratefully acknowledged.
REFERENCES
1. Jablonska S: Histopathology of scleroderma. Scleroderma
and Pseudoscleroderma. Edited by S Jablonska. Warsaw,
Polish Medical Publishers, 1975, pp 191-233
2. Cannon PJ, Hassar M, Case DB, Casarella WJ, Sommers
SC, LeRoy EC: The relationship of hypertension and
renal failure in scleroderma (progressive systemic sclerosis) to structural and functional abnormalities of the
renal cortical circulation. Medicine 53:1 4 6 , 1974
3. Maricq HR, LeRoy EC: Patterns of finger capillary abnormalities in connective tissue disease by “wide-field”
microscopy. Arthritis Rheum 16:619-628, 1973
4. Maricq HR, Spencer-Green G, LeRoy EC: Skin capillary
abnormalities as indicators of organ involvement in
scleroderma (systemic sclerosis), Raynaud‘s syndrome,
and dermatomyositis. Am J Med 615362-870, 1976
5. Maricq HR, Gordon G, LeRoy EC: Studies in patients
with connective tissue disorders, Ninth European Conference on Microcirculation, Antwerp, 1976. Bibl Anat
16:135-141, 1977
6. Maricq HR, Blume RS, LeRoy EC: Wide-field study of
nailfold capillary bed in disorders of connective tissue.
Sixth European Conference on Microcirculation, Aalborg, 1970. 1971, pp 116-122
7. Maricq HR: “Wide-field” photography of nailfold capillary bed and a scale of plexus visualization scores (PVS).
Microvasc Res 2:335-340, 1970
8. Maricq HR: Variations in the skin microvascular patterns
of the hand, Ninth European Conference on Microcirculation, Antwerp, 1976. Bibl Anat 16:164169, 1977
9. Redisch W, Messina EJ, Hughes G, McEwan C: Capillaroscopic observations in rheumatic diseases. Ann Rheum
Dis 29:44253, 1970
10. Maricq HR, Weinberger AB, LeRoy EC: Early detection
of scleroderma by in vivo capillary microscopy. In preparation
11. Bennett RM, OConnell DJ: The arthritis of mixed connective tissue disease. Ann Rheum Dis 37:397403, 1978
12. Bennett RM, Bong DM, Spargo BH: Neuropsychiatric
problems in mixed connective tissue disease. Am J Med
65:955-962, 1978
13. Lewis T: Notes on scleroderma (dermatornyositis). Br J
Dermatol 52:233-242, 1940
14. Banker BQ, Victor M: Dermatomyositis (systemic angiopathy) of childhood. Medicine 45:26 1-289, 1966
CAPILLARY MICROSCOPY IN SCLERODERMA
15. Masi AT, Rodnan GP, Medsger TA Jr, Fries JF, Altman
RD, McShane DJ, Sharp GC, Mackenzie AH, LeRoy
EC, Brown BW Jr, D’Angelo WA: Clinical criteria for
early diagnosed systemic sclerosis: preliminary results of
the ARA Multicenter Cooperative Study. Arthritis
Rheum 21576-577. 1978
189
16. Masi AT, Medsger TA Jr, Rodnan GP, Fries JF, Altman
RD, Brown BW, DAngelo WA, LeRoy EC, Mackenzie
AH, McShane DJ, Sharp GC: Methodology and preliminary results of the scleroderma criteria cooperative study
of the American Rheumatism Association. In preparation
Thirty-Third Annual Stoneburner Lecture Series
The Medical College of Virginia, Department of Continuing Medical Education and the Division of
Immunology and Connective Tissue Diseases will sponsor the 33rd Annual Stoneburner Lecture
Series, “Immunology and Immune Complexes,” April 11 and 12, 1980 in the Baruch Auditorium
of the Medical College of Virginia in Richmond. This is approved for 13 AMA Category I credit
hours.
For further information contact Kathy E. Johnson, Department of Continuing Education, Box 48,
MCV Station, Richmond VA 23298. Telephone: 804 786-0494.
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