ARTHRITIS & RHEUMATISM

Vol. 44, No. 3, March 2001, pp 735738

2001, American College of Rheumatology

LETTERS
NCM was performed as previously described (6,8). All
digits of both hands were examined with an SR stereomicroscope (Carl Zeiss, Montreal, Quebec, Canada) at 850
magnification using a cool source of illumination, and the
following were recorded: degree of capillary dilatation (0
normal; 1 borderline [2 normal diameter]; 2 definitely
dilated [2 but 4 normal diameter]; 3 extremely
dilated [4 normal diameter]) and avascular areas (A no
capillary loss; B rare avascular areas; C moderate
capillary loss; D extensive capillary loss). The capillary
origin of clinically visible telangiectasias of the hands was
confirmed by NCM. In our patient population, the specificity
of grade 2 or 3 capillary dilatations for SSc ranges from 95.6%
to 100%, as determined in studies using controls with primary
RP (n 507), systemic lupus erythematosus (SLE; n 27),
and rheumatoid arthritis (RA; n 20). All of the SLE and RA
controls were selected because they had RP. In studies using
the same controls, the specificity of grade C or D avascular
areas for SSc ranges from 93.1% to 100%.
As expected, all patients (100%) in the diffuse and
intermediate SSc subsets were ACR. However, in the limited
SSc subset, only 51 patients (33.6%) were ACR. Thus, 101
patients (66.4%) diagnosed by expert clinicians as having
limited SSc could not be classified as having SSc according to
the ACR 1980 criteria. No significant differences were observed between the limited SSc ACR and limited SSc ACR
groups in the proportion of women (92% versus 84.1%,
respectively), age at SSc onset (mean SD 38.4 14.3 years
versus 41.2 13.6 years), age at first evaluation (mean SD
50.5 12.5 years versus 51 11.3 years), or frequency of
clinically visible capillary telangiectasias of the hands, face,
lips, or tongue (62.7% versus 50.4%), capillary dilatations of
grades 0 and 1 (30.6% versus 34.7%), or of grades 2 and 3
(69.4% versus 65.2%), and presence of ACA (56.8% versus
50%).
In contrast, several clinical variables were significantly
more common in the limited SSc ACR group: digital pitting
scars (86.2% versus 0%; P 0.001), pulmonary fibrosis (11.7%
versus 0%; P 0.01), esophageal involvement (62.7% versus
34.6%; P 0.01), and calcinosis (45.1% versus 20.8%; P
0.01). More severe capillary loss was also significantly more
common in the limited SSc ACR versus the limited SSc
ACR group: 20.4% versus 45.2% for grade A or B avascular
areas, and 79.6% versus 54.7% for grade C or D avascular
areas (P 0.05).
To determine whether the sensitivity of the ACR
criteria for limited SSc could be improved, we computed the
sensitivities generated by addition of single clinical variables as
novel minor criteria, selected because their frequency was
equal or greater in the limited SSc ACR group. Figure 1 is a
regression tree showing the best improvement in sensitivity.
Introduction of grade 2 or 3 dilated capillaries improved the
sensitivity from 33.4% to 74.3%. The sensitivity further improved to 82.9% by adding grade C or D avascular areas, and
to 88.8% with clinically visible capillary telangiectasias. Finally,
the presence of ACA increased the sensitivity to 91.5%.
Due to the exclusion of a large number of patients with
limited SSc, accounting for 39% of our SSc cohort, the

Updating the American College of Rheumatology

preliminary classification criteria for systemic
sclerosis: addition of severe nailfold capillaroscopy
abnormalities markedly increases the sensitivity for
limited scleroderma
To the Editor:
We read with interest the article by Poormoghim et al
(1), in which they note that some patients with systemic
sclerosis (SSc) have disease that does not satisfy the American
College of Rheumatology (ACR; formerly, the American
Rheumatism Association) preliminary classification criteria
for definite SSc (2). Poormoghim and colleagues suggest that
the ACR classification criteria for SSc should be revised to
more adequately incorporate such patients (1). We concur with
their view and wish to share data showing our approach to this
issue.
The ACR classification criteria for SSc were not
designed for diagnostic purposes but rather with the intent to
establish a standard for definite disease in order to permit
comparison of groups of patients from different centers (2).
However, these criteria are perceived as diagnostic criteria (3)
and thus are often used by clinicians to diagnose SSc. Yet, like
Medsger (4) and others, we have observed that the ACR
criteria paradoxically exclude certain patients who have been
diagnosed by experienced clinicians as having definite SSc.
Therefore, we wished to evaluate the potential diagnostic value
of ACR criteria in our SSc cohort. Furthermore, given that the
ACR criteria were published 20 years ago, we wanted to
determine whether addition of more recently described SSc
features, such as nailfold capillary microscopy (NCM) features,
could increase their sensitivity.
Between 1984 and 1999, 259 consecutive French Canadian patients at the Connective Tissue Diseases Clinics,
Notre-Dame Hospital (5,6) were diagnosed by expert clinicians
(DC, J-RG, FJ, AR, ER, J-LS) as having definite SSc. The
clinical diagnosis of SSc was made without awareness of NCM
or anticentromere antibody (ACA) test results. Patients were
evaluated at first visit with a standard clinical, visceral extension, and NCM protocol encompassing 215 variables computerized into an Access database. They were categorized into 3
SSc subsets according to a slightly modified version of the
definitions described by Barnett et al (7), based on extent of
sclerodermatous skin involvement: diffuse (must include trunk
involvement; 29 patients), intermediate (must include upper
extremities proximal to metacarpophalangeal [MCP] joints
without trunk involvement; 78 patients), and limited (sclerodactyly only, plus Raynauds phenomenon [RP]; 152 patients).
Patients with overlap syndrome features were not included in
this classification. Patients were further classified as fulfilling
the ACR 1980 preliminary criteria for SSc (ACR) or not
(ACR), based on the presence or absence of the major
criterion, i.e., sclerodermatous skin involvement proximal to
MCP joints (including facial skin thickening), or 2 or more of
the minor criteria: 1) sclerodactyly, 2) digital pitting scars or
loss of substance of the distal finger pad, and 3) bibasilar
pulmonary fibrosis (2).
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LETTERS

Figure 1. Regression tree showing the sensitivity of possible minor criteria additions to the American College of
Rheumatology (ACR; formerly, the American Rheumatism Association) criteria for systemic sclerosis (SSc), as
applied to patients with limited SSc at first evaluation. Patients (n 152) were diagnosed as having limited SSc
by expert clinicians. All patients had Raynauds phenomenon plus the 1980 minor criterion of sclerodactyly.
Patients with 2 minor criteria, i.e., sclerodactyly plus 1 of these novel criteria, are designated ACR. Patients with
sclerodactyly as the only minor criterion are designated ACR.

sensitivity of the ACR criteria is low. Our data support the

view of Poormoghim et al (1) and previous findings by
Medsger (4) emphasizing the need to revise the ACR criteria
to more adequately incorporate patients with limited SSc.
These results suggest that the diagnostic sensitivity of ACR
criteria may be markedly improved by addition of simple
clinical variables, including NCM abnormalities and ACA
positivity, as novel minor criteria. These variables were not
included in the original ACR criteria, because they were
described after publication of the criteria. They should be
evaluated in a multicenter trial aimed at revising the 1980
criteria.
Supported by Sclerodermie Quebec.
Lilian Scussel Lonzetti, MD
France Joyal, MD, FRCPC
Jean-Pierre Raynauld, MD, FRCPC
Andre Roussin, MD, FRCPC
Jean-Richard Goulet, MD, FRCPC
ric Rich, MD, FRCPC
E
Denis Choquette, MD, FRCPC
Yves Raymond, PhD
Jean-Luc Senecal, MD, FRCPC
Notre-Dame Hospital
Centre Hospitalier de lUniversite de Montreal
Montreal, Quebec, Canada

1. Poormoghim H, Lucas M, Fertig N, Medsger TA Jr. Systemic

sclerosis sine scleroderma: demographic, clinical, and serologic
features and survival in forty-eight patients. Arthritis Rheum 2000;
43:44451.
2. Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee.
Preliminary criteria for the classification of systemic sclerosis
(scleroderma). Arthritis Rheum 1980;23:58190.
3. Wigley FM. Systemic sclerosis: clinical features. In: Klippel JH,
Dieppe PA, editors. Rheumatology. Philadelphia: Mosby; 1998. p.
7.9.113.
4. Medsger TA Jr. Comment on scleroderma criteria cooperative
study. In: Black CM, Myers AR, editors. Current topics in rheumatology: systemic sclerosis (scleroderma). New York: Gower; 1985. p.
167.
5. Weiner ES, Earnshaw WC, Senecal JL, Bordwell B, Johnson P,
Rothfield NF. Clinical associations of anticentromere antibodies
and antibodies to topoisomerase I: a study of 355 patients. Arthritis
Rheum 1988;31:37885.
6. Joyal F, Choquette D, Roussin A, Senecal JL. Evaluation of the
severity of systemic sclerosis by nailfold capillary microscopy in 112
patients. Angiology 1992;43:20310.
7. Barnett AJ, Miller MH, Littlejohn GO. A survival study of patients
with scleroderma diagnosed over 30 years (19531983): the value of
a simple cutaneous classification in the early stages of the disease.
J Rheumatol 1988;15:27683.
8. Maricq HR. Widefield capillary microscopy: technique and rating
scale of abnormalities seen in scleroderma and related disorders.
Arthritis Rheum 1981;24:115965.

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737

Possible role of antiidiotypes in the loss of anti

topoisomerase I antibodies: comment on the article by
Kuwana et al
To the Editor:
We read with great interest the article by Kuwana et al
(1) reporting on a subset of antitopoisomerase I antibody
(antitopo I)positive patients with systemic sclerosis who lost
this autoantibody during their disease course, independent of
immunosuppressive treatment. These patients, referred to as
group 1, had a favorable clinical outcome compared with
patients who were persistently positive for this autoantibody
(group 2). Topo I reactivity of group 1 patients circulating
lymphocytes, isolated from an antibody-negative blood sample,
was intermediate between that observed with healthy donors
and that with group 2 patients. Kuwana et al attribute the
disappearance of antitopo I to a loss of antigenic stimulation
of topo Ireactive lymphocytes, rather than to their elimination.
We would like to propose an alternative theory to
account for the disappearance of antitopo I in these patients,
based on antiidiotypic regulation of another disease-specific
autoantibody, antiribosomal P. These antibodies are detected
by conventional assays only in patients who have systemic lupus
erythematosus (SLE) or overlap diseases with SLE (2). Interestingly, we identified these antibodies in all healthy individuals sera after treatment with immobilized ribosomal P protein
(3,4). Antiidiotypic antibodies, which are displaced by this
treatment, mask antiribosomal P antibodies, thereby preventing their detection by conventional assays (5). SLE patients
who persistently lack antiribosomal P antibodies also have
masking antiidiotypes, whereas those who are persistently
positive for antiribosomal P antibodies have absent or dysfunctional antiidiotypes (5). We also identified a subset of antiribosomal P antibodypositive patients (n 7) who lost these
antibodies during their disease course. Covert antiribosomal P
antibodies and their antiidiotypes were recoverable from their
sera when overt antiribosomal P antibodies were not demonstrable. Thus, we hypothesize that antiidiotypes contribute to
the disappearance of antiribosomal P antibodies in these
patients.
We would like Kuwana and colleagues to consider the
possibility that antiidiotypes to antitopo I fulfill a similar role
in topo Ispecific autoimmunity. These antibodies could prevent the serologic detection and in vitro production of anti
topo I in healthy individuals and account for their loss in group
1 patients. Regulatory antiidiotypes could be responsible for
the delayed antigen-specific T lymphocyte proliferation and
decreased T lymphocyte precursor numbers in healthy individuals and group 1 patients. If this scenario is accurate, then
antitopo I autoantibodies would join the growing list of
autoantibodies that are regulated by antiidiotypes, e.g., antiDNA, antimitochondrial antibodies, and a variety of organspecific autoantibodies (6).
Haraldine A. Stafford, PhD, MD
University of Oklahoma Health Sciences Center
Oklahoma Medical Research Foundation
and Department of Veterans Affairs
Zi-Jian Pan, MD
Camille J. Anderson, MS
Oklahoma Medical Research Foundation
Oklahoma City, OK

1. Kuwana M, Kaburaki J, Mimori T, Kawakami Y, Tojo T. Longitudinal analysis of autoantibody response to topoisomerase I in
systemic sclerosis. Arthritis Rheum 2000;43:107484.
2. Elkon KB, Bonfa E, Brot N. Antiribosomal antibodies in systemic
lupus erythematosus. Rheum Dis Clin North Am 1992;18:37790.
3. Stafford HA, Anderson CJ, Reichlin M. Unmasking of antiribosomal P autoantibodies in healthy individuals. J Immunol
1995;155:275461.
4. Anderson CJ, Neas BR, Pan Z, Taylor-Albert E, Reichlin M,
Stafford HA. The presence of masked antiribosomal P autoantibodies in healthy children. Arthritis Rheum 1998;41:3340.
5. Pan Z, Anderson CJ, Stafford HA. Anti-idiotypic antibodies prevent the serologic detection of anti-ribosomal P autoantibodies in
healthy adults. J Clin Invest 1998;102:21522.
6. Stafford HA, Reichlin M. Dysregulation of the idiotype network in
autoimmune diseases. In: Paul S, editor. Contemporary immunology: autoimmune reactions. Totowa, NJ: Humana Press; 1999. p.
15776.

Reply
To the Editor:
We thank Dr. Stafford and colleagues for their valuable comments on our study of longitudinal antitopo I
responses in patients with systemic sclerosis (SSc). We attributed the disappearance of serum antitopo I in the group 1
patients to a loss of antigenic stimulation that activates topo
Ireactive T and B cells. Dr. Stafford and coworkers propose
possible alternative explanations.
Stafford et al raise 2 different points. First, they suggest
a possible interpretation of the negative serum antitopo I
findings in group 1 patients, i.e., that covert antitopo I is still
present in sera, but antiidiotypes prevent their detection of
conventional serologic assays. Unfortunately, we have not
examined masked anti-topo I after treatment of group 1 sera
with immobilized topo I, and there is no reported study
examining antiidiotypes to antitopo I in sera from SSc
patients or healthy individuals. However, analysis of antitopo
I idiotypes by Vazquez-Abad et al showed the presence of both
cross-reactive and private idiotypes (1). In addition, the majority of antitopo Ipositive SSc sera contain heterogeneous
antibodies directed against several distinct epitopes, including
continuous and conformational epitopes (2,3). These findings
strongly suggest that antitopo I in SSc sera are heterogeneous
in terms of idiotypic expression and antigenic specificity.
Therefore, it is unlikely that induction of antibodies to 1 or a
few idiotypes alone prevents the serologic detection of the
entire range of antitopo I antibodies, although multiple types
of antiidiotypes to antiribosomal P have been shown to exist in
some individuals (4).
Stafford and colleagues also suggest an alternative
theory to account for the disappearance of antitopo I, i.e.,
that autoreactive T and B cell responses to topo I are
suppressed by antiidiotypic regulation, rather than a loss of
antigenic stimulation. In this regard, it has been shown that
antiidiotypes suppress antibody production from B cells by
crosslinking B cell receptors (5,6). In addition, we have re-

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ported that topo Ispecific B cells are acting not only as

antitopo Iproducing cells but also as efficient antigenpresenting cells that activate topo Ireactive CD4 T cells (7).
Therefore, antiidiotypes may inhibit antigen uptake by blocking the antigen-binding site of B cell receptors, resulting in
insufficient presentation of cryptic epitopes to topo
Ireactive CD4 T cells. The delayed kinetics of antigeninduced T cell proliferation and the decreased T cell precursor
frequencies in group 1 patients after loss of antitopo I could
be explained by this regulatory action of antiidiotypes. On the
other hand, we recently identified CD8 T cells that specifically killed topo Ispecific CD4 T cells in SSc patients with
antitopo I, probably by recognition of the unique determinants on the T cell receptor. It is believed that immune
tolerance to the variable regions in the T cell receptors and
immunoglobulins that determine antigen binding specificity
does not develop, since during the neonatal period these
unique binding regions are present at levels that are too low to
induce tolerance. Individual T cell receptors and immunoglobulins are therefore immunogenic by virtue of these unique
sequences, and immune responses to these idiotypes are
capable of influencing the outcome of an immune response.
Taken together, these observations indicate that further studies examining immune responses to the idiotypes of
both T cell receptors and immunoglobulins are necessary to

LETTERS

understand mechanisms regulating autoantibody responses in

patients with autoimmune diseases.
Masataka Kuwana, MD
Keio University School of Medicine
Junichi Kaburaki, MD
Tokyo Electric Power Company Hospital
Tokyo, Japan
1. Vazquez-Abad D, Pascual V, Zanetti M, Rothfield NF. Analysis of
human antitopoisomerase I idiotypes. J Clin Invest 1993;93:
130113.
2. Kuwana M, Kaburaki J, Mimori T, Tojo T, Homma M. Autoantigenic epitopes on DNA topoisomerase I: clinical and immunogenetic associations in systemic sclerosis. Arthritis Rheum 1993;36:
140613.
3. Kuwana M, Kaburaki J, Medsger TA Jr, Wright TM. An immunodominant epitope on DNA topoisomerase I is conformational in
nature: heterogeneity in its recognition by systemic sclerosis sera.
Arthritis Rheum 1999;42:117988.
4. Pan Z, Anderson CJ, Stafford HA. Anti-idiotypic antibodies prevent the serologic detection of anti-ribosomal P autoantibodies in
healthy adults. J Clin Invest 1998;102:21522.
5. Rajewsky K, Takemori T. Genetics, expression, and function of
idiotypes. Annu Rev Immunol 1983;1:569607.
6. Geha RS. Idiotypic-anti-idiotypic interactions in man. Am J Dis
Child 1985;139:41720.
7. Kuwana M, Medsger TA Jr, Wright TM. TB cell collaboration is
essential for the autoantibody response to DNA topoisomerase I in
systemic sclerosis. J Immunol 1995;155:270314.