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Number 7, July 1995, pp 1024-1026
0 1995, American College of Rheumatology
Lack of associata between antihistone antibodies and
pulmonary fibrosis in patients with systemic sclerosis:
comment on the article by Sat0 et a1
To the Editor:
We read with interest the article by Sat0 et a1 (l),
who reported on the occurrence of antihistone antibodies
(AHA) in the serum of patients with systemic sclerosis (SSc)
and on the clinical association with pulmonary fibrosis. We
would like to comment on their report, especially since some
of our own data conflict with theirs.
TOaddress the questions of whether AHA antibodies
are a frequent finding in patients with SSc and whether the
presence of these antibodies is associated with pulmonary
fibrosis, we measured serum AHA of the IgG isotype, using
an enzyme-linked immunosorbent assay (ELISA) that detects H I , H2a, H2b, H3, and H4 antigens. Sera from 74
patients with SSc according to the criteria of the American
College of Rheumatology (formerly, the American Rheumatism Association (2)) were investigated. Clinical data were
obtained during a clinic visit and/or retrospectively by
cumulative evaluation of medical charts and records. Therefore, the dates of clinical diagnosis and of serum sampling for
ELISA did not always coincide. Thirty (40.5%) of these
patients had pulmonary fibrosis; the diagnosis of pulmonary
fibrosis was confirmed by either chest radiography, computed tomography, or biopsy.
In accordance with the data presented by Sat0 et al,
we found a high frequency of AHA positivity in the serum of
patients with SSc. The frequency of positive ELISA results
was even higher among our patients than among theirs (47%
[35 of 741 versus 29% [27 of 921). Further differentiation
according to specific scleroderma-related autoantibodies revealed the frequency of AHA to be 46% (21 of 46) in patients with anti-topoisomerase I antibodies, 67% (10 of 15)
in patients with anti-U1 RNP antibodies, 33% (2 of 6) in
patients with anti-PM-Scl antibodies, and 25% (1 of 4) in
patients with anticentromere antibodies. In contrast to the
findings of Sat0 et al, however, we found a significant negative
association of AHA with pulmonary fibrosis. Nine of the 30
SSc patients with pulmonary fibrosis (30%) had AHA, versus
25 of the 44 without pulmonary fibrosis (57%) (P = 0.0326).
We believe it is of interest that AHA can be found in
patients with SSc, in addition to their well-known occurrence in systemic lupus erythematosus and juvenile rheumatoid arthritis (3-5). However, our data do not support the
notion that pulmonary fibrosis is associated with the occurrence of AHA. Unlike Sat0 et al, we tested only for the IgG
isotype of AHA and not for IgM AHA, although their data
do not suggest a differential relationship of IgG versus IgM
to the development of pulmonary fibrosis. More important,
however, may be the difference in disease duration between
our patients (mean duration of SSc 6.5 years) and those studied
by Sat0 and colleagues (mean 8.8-10.5 years, depending on the
SSc subset). It is possible that this difference is the reason for
the contradictory results concerning the association of AHA
with pulmonary fibrosis, especially since pulmonary fibrosis is
reported to be a late (though, once established, a considerably
stable) finding over time. Our data, however, do not support
this explanation, since we did not find any statistically significant differences in disease duration between patients with
pulmonary fibrosis who had versus those who did not have
AHA. Reported racial differences in the prevalence of pulmonary fibrosis in patients with SSc (6,7) might also account for
the observed differences. Further studies should therefore
include prospective follow-up examinations for serum AHA in
patients with SSc, as well as further differentiation of the
molecular subunits recognized by AHA-positive sera, to address the question of whether certain subsets of AHA may
confer increased long-term risk for the development of pulmonary fibrosis.
Supported by the Verein zur Forderung der Rheumuforschung bei
der Rheumaklinik Aachen e.V.
Thomas Dick, PhD
Peter Bartz-Bazzanella, MD
Ekkehard Genth, MD
Rheumaforschungsinstitut und Rheumaklinik
Aachen, Germany
1. Sat0 S, Ihn H, Kikuchi K, Takehara K: Antihistone antibodies in
systemic sclerosis: association with pulmonary fibrosis. Arthritis
Rheum 37:391-394, 1994
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 2331-590, 1980
Tan EM: Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol
44:93-151, 1989
Cohen MG, Pollard KM, Webb J: Antibodies to histones in
systemic lupus erythematosus: prevalence, specificity, and relationship to clinical laboratory features. Ann Rheum Dis 51:61-66,
Malleson PN, Fung MY, Petty YRE, Mackinnon MJ, Schroeder
ML: Autoantibodies in chronic arthritis of childhood: relations
with each other and with histocompatibility antigens. Ann
Rheum Dis 51:1301-1306, 1992
Livingston JZ, Scott TE, Wigley FM, Anhalt GJ, Bias WB,
McLean RH, Hochberg MC: Systemic sclerosis (scleroderma):
clinical, genetic and serologic subsets. J Rheumatol 14512-518,
Kuwana M, Kaburaki J, Okano Y, Tojo T, Homma M: Clinical
and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis Rheum
37:75-83, 1994
To the Editor:
We thank Dr. Dick and colleagues for their interest in
our article. They have confirmed our results showing the
presence of AHA in sera from patients with SSc. However,
they found a much higher percentage of IgG-isotype AHA in
their SSc patients (47%) than was found in our study (19 of
92, 21%). Several previous studies have shown the prevalence of AHA in SSc to be 5-25% (1-3), similar to our data.
Furthermore, Dick et a1 detected AHA in 46% of SSc
patients who were positive for anti-topoisomerase I antibody (anti-top0 I) and in 67% of SSc patients positive for
a n t i 4 1 RNP antibody, frequencies much higher than were
found in our study (36% and 8%, respectively).
Since histone is a basic protein and is heavily positively charged (4), nonspecific binding to histones coated on
the plate frequently occurs, leading to high levels of falsepositive reactions. We set the cutoff value for determination
of positivity as 3 SD above the mean normal binding level,
to prevent such false-positive reactions. Furthermore, by
immunoblotting using total histones as substrate, we confirmed the presence of IgG-type AHA in the serum samples
that were IgG AHA positive by ELISA. Although in their
letter Dick et a1 do not explain in detail their methods of
detecting AHA, differences in experimental procedures and
in data analysis might lead to the differences in findings of
AHA positivity.
Our study showed that the presence of IgG- and/or
IgM-type AHA correlated with pulmonary fibrosis in patients with diffuse cutaneous SSc (dcSSc) or in SSc patients
with anti-top0 I. Such an association was also found for IgG
AHA alone, as stated in our report. In contrast, Dick and
colleagues found a negative correlation between IgG AHA
and pulmonary fibrosis. Although this difference might be
due to the high frequency of AHA positivity in their SSc
patients, especially in those with anti-U1 RNP, a difference
in study populations might also account for the conflicting
results. In our study, the correlation of AHA with pulmonary fibrosis was observed only in patients with relatively
severe SSc, such as those with dcSSc or those who were
positive for anti-top0 I. We did not observe such an association in patients with limited cutaneous SSc (IcSSc) or in SSc
patients with a n t i 4 1 RNP. In contrast, Dick et a1 attempted
to identify the association in an overall group that included
patients with dcSSc, patients with IcSSc, and patients with
anti-U1 RNP.
Racial differences in study populations would be
another important factor that might explain the difference
between Dick and colleagues’ findings and ours. Although
the clinical significance of AHA has been extensively studied
in other autoimmune disorders such as systemic lupus erythematosus and juvenile chronic arthritis, it has not been
fully established to date. This suggests that clinical manifestations of AHA may be more subject to racial differences
than are those of other autoantibodies. Further studies
(especially prospective studies) will be needed to clarify the
clinical significance of AHA in SSC.
Shinichi Sato, MD, PhD
Manabu Fujimoto, MD
Kanako Kikuchi, MD, PhD
Hironobu Ihn, MD
Kazuhiko Takehara, MD, PhD
University of Tokyo
Tokyo, Japan
1. Rubin RL, Waga S: Antihistone antibodies in Systemic lupus
erythematosus. J Rheumatol SUPPI 14: 118-126, 1986
2. Aitkaci A, Monier JC, Mamelle N: Enzyme-linked hmunosorbent
assay for anti-histone antibodies and their presence in systemic
lupus erythematosus sera. J Immunol Methods 44:311-322, 1981
3. Costa C, Monier JC: Detection of antibodies to histones in
human systemic lupus erythematosus and in murine lupus-like
syndromes using micro-ELISA. Ann Immunol 134C:365-376, 1983
4. Sperling R, Wachtel EJ: The histones. Adv Protein Chem 34:l60, 1981
Stress fractures in rheumatoid arthritis: comment on
the article by Wei
To the Editor:
We read with interest the article by Wei describing
the occurrence of stress fractures of the distal fibula presenting as monarticular flares in patients with rheumatoid arthritis (RA) (l), and we concur with Dr. Wei about the need to
distinguish between these pathologic fractures and a monarticular flare in RA patients. We have had the opportunity
to report such occurrences and to underscore the value of
bone scintigraphy for diagnosing such events in patients in
whom plain radiography findings are inconclusive (2,3). In
fact, our 4 patients all presented with what appeared to be an
inflammatory/infectious process and were treated initially
either with an increased dosage of corticosteroids or with
parenteral antibiotics. More recently, 1 of these 4 patients
presented with a sausage digit of approximately 4 days
duration, while her other joints were essentially unchanged;
on examination, point tenderness was found over the distal
portion of the corresponding metatarsal bone, and a radiograph confirmed the presence of a fracture. The swelling and
erythema, however, were manifested distal to the fracture,
suggesting involvement of the digit itself. Interestingly, this
patient had herself already considered the correct diagnosis,
since she was able to distinguish the features of a flare from
those of a fracture based on her previous experience with a
fractured ulna.
In short, stress fractures in RA patients are not
uncommon, may manifest with “inflammatory” changes,
and may not be demonstrated on plain radiographs. We are
concerned that the recent publication included only references published more than 10 years ago, giving the impression that stress fractures in patients with RA are uncommon.
Graciela S. A l a r c h , MD, MPH
Karin V . Straaton, MD
The University of Alabama at Birmingham
1. Wei N: Stress fractures of the distal fibula presenting as mon-
articular flares in patients with rheumatoid arthritis. Arthritis
Rheum 37:1555-1556, 1994
2. Straaton KV, L6pez-MCndez A, Alarc6n GS: Insufficiency fractures of the distal tibia misdiagnosed as cellulitis in three patients
with rheumatoid arthritis. Arthritis Rheum 34:912-915, 1991
3. Mikhail IS, Bernreuter WK, Alarc6n GS: Insufficiency fracture
of the distal ulna presenting as cellulitis (letter). Arthritis Rheum
36:1027-1028, 1993
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