Systemic Sclerosis-Associated Myopathy

BRIGITTE RANQUE,a FRANÇOIS-JÉRÔME AUTHIER,b

ALICE BEREZNE,a LOÏC GUILLEVIN,a AND LUC MOUTHONa
a ParisDescartes University, Faculty of Medicine Paris Descartes, UPRES EA
4058, Department of Internal Medicine, French National Reference Center for
Systemic Sclerosis and Vasculitides, Cochin Hospital, Assistance Publique des
Hôpitaux de Paris (AP-HP), Paris, France
b Reference
Center for Neuro-muscular Diseases, Henri Mondor Hospital,
AP-HP, INSERM U 841, Paris 12 University, Créteil, France

ABSTRACT: Skeletal muscle involvement is a common feature in sys-

temic sclerosis (SSc) because muscle weakness is found in up to 90%
SSc patients when systematically assessed. Muscle clinical, biological,
and electromyographic features are similar to those of polymyositis or
dermatomyositis, except for a higher proportion of mild symptoms. SSc-
associated myopathy is more prevalent in diffuse SSc and is also asso-
ciated with cardiomyopathy. The pathophysiological process leading to
SSc-associated myopathy is likely to be complex, given the heterogene-
ity of pathological muscle findings, including stigma of microangiopathy,
and also inflammatory infiltrate in about half of the cases and interstitial
fibrosis. Conflicting results have been reported regarding the correlation
between clinicobiological presentation and pathological muscle features,
nevertheless there is a general agreement that histologically proven in-
flammatory myopathies usually regress under high-dose corticosteroid
therapy, or even low dose in case of positive anti-PM/Scl antibody. In
contrast, noninflammatory myopathies often result in milder clinical ex-
pression but do not respond to immunosuppressive treatment.

KEYWORDS: systemic sclerosis; myopathy; myositis; overlap syndrome

INTRODUCTION

Systemic sclerosis (SSc) is a connective tissue disease characterized by

excessive collagen deposition in the dermis and internal organs and by vascular
hyper-reactivity and obliterative microvascular phenomena.1 Patients with SSc
are classified according to the extent of skin involvement: limited SSc (lSSc),
with no detectable skin involvement; limited cutaneous SSc (lcSSc),2 with skin
Address for correspondence: Luc Mouthon, M.D., Ph.D., Department of Internal Medicine, Cochin
Hospital, 27 rue du Faubourg Saint-Jacques, 75679 Paris, Cedex 14, France. Voice: +33-01-58-41-21-
34; fax: +33-01-58-41-14-50.
luc.mouthon@cch.aphp.fr

Ann. N.Y. Acad. Sci. 1108: 268–282 (2007). 

C 2007 New York Academy of Sciences.

doi: 10.1196/annals.1422.029
268
RANQUE et al. 269

involvement essentially limited to the hands and face; and diffuse SSc (dSSc),
with proximal skin involvement.3 In patients with lcSSc, visceral involvement
is rare, and the prognosis is good, with the exception of the 8–12% of patients
in whom pulmonary arterial hypertension eventually develops.4,5 Patients with
dSSc experience visceral involvement, which is responsible for reduced life
expectancy.6 In addition to diminishing life expectancy, SSc is responsible for
skin, tendon, joint, and vessel damage, which leads to disability, handicap, and
worsening of quality of life.7

PREVALENCE OF MUSCLE INVOLVEMENT

IN SYSTEMIC SCLEROSIS C

Skeletal muscle involvement in SSc patients was first reported in 1876,8

and was considered as a minor component of the disease in the very initial
SSc series.9 However, myopathy turned out to be a common feature in the
subsequent SSc series, with a prevalence ranging from 16% to 81%.10–19 This
wide range of prevalence reflects the high degree of heterogeneity of crite-
ria used to define muscle involvement that can include clinical, biological,
electromyographic (EMG), and/or histological evidence for muscle abnormal-
ities.20 Clinical criteria themselves vary from simple myalgias or fatigue to
significant muscle weakness (which can also be defined by various criteria)
(TABLE 1). Moreover, the reported prevalence of skeletal muscle involvement
also depends on how systematically it is sought. Thus, in the series of Medsger
et al.,10 the vast majority (90%) of SSc patients had a proximal muscle weak-
ness upon careful clinical examination, whereas only 20% of them complained
of muscle-related symptoms. Interestingly, systematic muscle pathological
studies report a high prevalence of skeletal muscle involvement, particularly
in postmortem series (10/19 autopsy cases in Ref. 10). Another potential fac-
tor of discrepancy is the exclusion (or not) of scleroderma overlap syndromes
from the SSc sample because inflammatory myopathies are a common fea-
ture in these syndromes.21 Moreover, a high proportion of the so-diagnosed
“polymyositis/SSc overlaps” in the ancient series probably corresponded to
nonspecific myositis22 primarily associated with SSc, as this will be discussed
later.

THE NEED FOR A SPECIFIC CLASSIFICATION

One of the most important problems when analyzing the literature related
to SSc-related myopathy is the absence of definite criteria for the diagnosis of
such an entity. Because clinical, biological, EMG, and pathological features are
very heterogeneous from one study to another, it is highly probable that SSc-
associated myopathy actually includes several distinct entities with different
 270

TABLE 1. Clinical studies of SSc-associated myopathies

(a) Clinical, biological, EMG features
Number of SSc Criteria for skeletal Number of patients Muscle CPK and Aldolase Positive EMG
Reference patients (D/L) myopathy (SM) (D/L) with SM weakness elevation (myopathic)
Medsger et al.10 53 (NA) Muscle weakness 42 (NA) 42/53 (79%) 3/53 (6%) NA
20/35 (57%)
Thompson et al.11 15 (NA) Muscle weakness or MB+ 14/15 (NA) 3/15 (20%) NA 4/15 (27%)
or EMG+
Clements et al.12 24 (22/2) Muscle weakness or EMG+ S: 19 (17/2) S: 15/19 (81%) S: 37%/74% S: 18/19 (95%)
or CPK C: 4 (4/0) C: 4/4 (100%) C: 100%/80% C: 4/4 (100%)
West et al.13 47 (31/16) CPK+ at least: EMG, 8 (8/0) NA 8/8 (100%) 5/8 (63%)
muscle weakness, MB+ 3 SM + CM 7/8 (88%)
Russell et al.15 28 (NA) Muscle weakness 9 (NA) 9/28 (32%) 3/9 (33%) 6/7 (86%)
NA
Ringel et al.24 14∗ (NA) Muscle weakness 14 (NA) 14 (100%) 8/12 (75%) 14/14 (100%)
NA
Follansbee et al.18 1,095 (NA) Muscle weakness+ at least 183 (NA) 39/39c (100%) 23/25c (92%) 13/16c (81%)
CPK, MB, EMG+ 39 SM + CM 10/22c (45%)
Averbuch-Heller et al.16 50 (NA) Muscle weakness+ at least 11 (NA) NA NA NA
CPK, MB, EMG+
Hietaharju et al.17 32 (23/9) >1 among CPK, EMG, 16 (NA) 16/32 (50%) 4/32 (13%) 6/18 (33%)
muscle weakness, MB+ NA
Continued.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
TABLE 1. Continued
(b) Muscle pathology, autoantibodies, and prognosis
RANQUE et al.

Reference Abnormal MB Muscle pathology Autoantibodies Prognosis and treatment

Medsger 14/36 Interstitial and perivascular (5) fibrosis: 13 NA NA
et al.10 Interstitial and perivascular (3) inflammatory
infiltrate: 8
Myofibril atrophy, necrosis, and degeneration: 8
Abnormal vessels: 8
Thompson 11/12 Increase in centrally placed nuclei: 14 ANA: 11/15 NA
et al.11 Atrophy: 7, interstitial fibrosis: 7
Phagocytic cell infiltrate: 2, necrosis,
regeneration, fat: 0
Mitochondrial abnormalities: 4, basal membrane
lamination++
Clements S: 3/3 S: fibrosis and variation in fibers size, S:1 RNP S: steady (1/19 had CS)
et al.12 0 inflammation
C: 4/4 C: variation in fiber size: 5, fibrosis: 1, C: 1 RNP, 1 Sm C: 3 (i ) good and 1 partial
inflammationi : 3 response to CS
(+necrosis: 2, +degeneration: 2)
West 6/6 Two mononuclear cell infiltrate, necrosis, 3/3 ENA 3 (i+c ) good response to CS
et al.13 degeneration, and regeneration (in 2 patients (40–100 mg/day)
with cardiomyopathy)i+c
Four mild inflammatory infiltrate, variability of (i+c ) 6 others: improved or steady, no
fiber size, few scattered angular fibers (1 treatment
patient with cardiomyopathyc )
Continued.
271
 272

TABLE 1. Continued
(b) Muscle pathology, autoantibodies, and prognosis
Reference Abnormal MB Muscle pathology Autoantibodies Prognosis and treatment
Russell — Quantitative evaluation of capillaries basal NA NA
et al.15 membrane thickness and diameter
Ringel NA/14 Vasculopathy: 7 (intimal proliferation + mild ANA: 2/14 NA
et al.24 increase endomysial, and/or perimysial
connective tissue: 7, perivascular inflammation
5, necrotizing vasculitis 1)
“PM”: 6 (variation fiber size, interstitial
mononuclear inflammation, myophagocytosis)
Variation in fiber size + increase internalized
nuclei: 1
Follansbee 13/16c Varying size: 8, necrosis: 9, degeneration: 9, ANA: 18/22 NA
et al.18 atrophy: 7, regeneration 5, inflammation 2 Scl70, 1 AC
(interstitium: 6, vessels: 4) 1 RNP, 1 Sm
Fibrosis (interstitium: 4, vessels: 2), vessels 1 PM/Scl
thickening: 3
Averbuch- 7/7 4 “simple” (S): no biopsy NA 4/4 S steady, no treatment
Heller 5 “PM”: inflammatory myopathy (no further 4/5 “PM” and 1/2 IBM
et al.16 detail) responded to CS
2 IBM : inclusion body myositis
Hietaharju 2/3 Inflammatory myopathy: 2/3 NA NA
et al.17
∗ Patients with skeletal myopathy specifically recruited.
SSc = systemic sclerosis; D = diffuse; L = limited; SM = skeletal myopathy; EMG = electromyogram; CPK = creatine phosphokinase; MB = muscle biopsy;
NA = not available; C = complicated; S = simple; CM = cardiomyopathy; ANA = antinuclear antibodies, CS = corticosteroids; ENA = antinucleolar antibodies;
AC = anticentromere; IBM = inclusion body myositis; RNP = ribonucleoprotein; PM = polymyositis; HD = high dose; Sm = Smith.
c Patients with SM and CM.
i Patients with muscle inflammation.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
RANQUE et al. 273

pathogenetic mechanisms involved and distinct outcomes. In 1978 Clements

et al. had proposed to differentiate two subsets of patients: those with “simple”
and those with “complicated” myopathy, mainly based on clinical, biologi-
cal, and EMG criteria.12 Their study consisted of 23 SSc patients with any of
the following muscular signs: weakness, muscle enzymes elevation, consistent
EMG study, or abnormal muscle biopsy. Nineteen of them presented with mild
clinical and biological symptoms, and stable course without specific treatment,
and were referred to as “simple myopathy.” Only three of them underwent a
muscle biopsy, which showed variation in fiber size and interstitial fibrosis.
The remaining four patients had a more acute and severe clinical presentation,
similar to the one observed in polymyositis or dermatomyositis, with high
levels of serum creatine phosphokinase (CPK) and important EMG abnormal-
ities. Three of them had pathological features of inflammatory myopathy and
an excellent response to corticosteroid therapy. This latter group was called
“complicated myopathies.”12 This classification has been used in several sub-
sequent papers.16,17,23 However, to date, a number of further series reporting
detailed clinical, biological, EMG, and pathological features did not support
such a dichotomist vision.10,11,18,24 In our opinion, the clinicobiological and
EMG presentation of the myopathy is certainly not sufficient to predict the
course of the muscle disease and the benefit of a specific treatment, as will be
discussed in the prognosis section.
Even when focusing on muscle pathological findings only, no clear-cut clas-
sification has emerged. Thus, as it will be discussed later on, inflammatory
infiltrate, necrosis, vascular abnormalities, and/or fibrosis may be observed,
but no association can be demonstrated between these different items. For
example, vascular abnormalities may be isolated or associated with inflamma-
tion and/or necrosis and/or with fibrosis, or absent.10,11,18,24 It is noteworthy
that all the quoted series were published more than 10 years ago, and none
of them included immunostaining studies. Therefore, new insights on the im-
munopathological nature of skeletal muscle involvement in SSc patients are
certainly needed before proposing any further classification.
More puzzling is the fact that SSc/polymyositis overlap syndrome and
SSc-associated myopathy are not clearly differentiated in this literature. It is
noteworthy that among connective tissue diseases commonly associated with
idiopathic inflammatory myopathies in overlap syndromes, SSc is the most fre-
quent, accounting for 42.6% of them in a series where 68 patients had overlap
inflammatory myopathy according to clinical and immunological criteria.25
Whether the association of an inflammatory myopathy and SSc constitutes
an SSc/polymyositis overlap syndrome or should be considered a SSc mani-
festation still remains controversial. However, the most recent studies in the
field of inflammatory myopathies show that the diagnosis of polymyositis
has long been overlooked using Bohan and Peter’s criteria,26 which do not
require muscle biopsy and a fortiori immunopathology. Using the current im-
munohistological criteria, most of the formerly so-called “polymyositis” would
274 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES

probably be diagnosed as nonspecific myositis associated with connective tis-

sue disorder.22,27 This point certainly has to be applied to the more specific
issue of myositis associated with SSc. Therefore immunopathological studies
are needed again to determine which of these myositis should be considered
as part of the disease.

CHARACTERISTICS OF SSC WITH MYOPATHY

It has been reported in several series that myopathy occur more frequently in
diffuse than in lcSSc. For example, the prevalences of skeletal muscle involve-
ment in diffuse and limited cutaneous forms were, respectively, 51% versus
12% in Tager et al.,28 20% versus 9% in Mimura et al.,19 and 26% versus 0%
in West et al.13 Three studies reported that heart involvement (characterized by
arrhythmias, conduction blocks, and/or left ventricular dysfunction) was more
frequent in SSc patients with skeletal myopathy (TABLE 1). West et al. reported
3 of 8 patients with dSSc and myositis presenting cardiomyopathy as compared
to none of the other SSc patients (23 diffuse and 16 lcSSc).13 Accordingly, in
Follansbee et al. series, 21% of 183 SSc patients with myopathy had a primary
cardiac involvement versus 10% of 912 SSc without myopathy.18 Interestingly,
skeletal muscle involvement associated with primary cardiomyopathy included
both myositis and noninflammatory myopathies, in similar proportions. How-
ever, in the absence of multivariate analysis, it was not possible to determine
whether these findings were independent or simply reflected the prominent
association of dSSc with myopathy. The association of myopathy with other
manifestations of SSc has rarely been studied. In a recent retrospective study,
including both diffuse and lcSSc patients, Mimura et al.19 confirmed the higher
prevalence of heart involvement in myopathy-associated SSc and reported a
higher frequency of pulmonary fibrosis, diffuse pigmentation of the skin, and
contractures of the phalanges in this group as compared to that of SSc pa-
tients without myopathy. As far as the immunological findings are concerned,
anti-PM/Scl and anti-ribonucleic protein (RNP) autoantibodies have been as-
sociated with a higher prevalence of myositis, as discussed in the autoantibody
section. Conversely, anticentromere antibodies have been found to be highly
“protective” for myositis in two recent studies.18,29

CLINICAL, BIOLOGICAL, AND EMG PRESENTATION

OF MYOPATHY

Muscle clinical symptoms are frequently mild in SSc patients. Fatigue is

one of the prominent complaint in patients with SSc and may be at least in
part imputable to muscle involvement in several cases, even though multiple
RANQUE et al. 275

other factors can be involved.30 When muscle strength was systematically as-
sessed in SSc patients, a severe motor deficiency was evidenced in a large
proportion of patients in two series with a large predominance of dSSc: 30%
when defined as a third or fourth grade in a four grades clinical scale12 or
43% when defined as a muscle strength <75% of normal performance.10 The
clinical presentation of SSc-associated myopathy shares many features with
polymyositis or dermatomyositis. The weakness is symmetrical, and mainly
involves proximal muscles, although distal weakness may be difficult to eval-
uate in the presence of severe skin sclerosis and the involvement of underlying
tissues that limit the motion of joints. In contrast, myalgias are less frequently
reported (5–15%).10,12,24
Muscle enzyme elevation is inconstant, ranging from 38% in SSc patients
with muscle weakness17 to 66% in histologically proved myopathies24 and is
often mild (<10 N). As observed in other myopathies, the combined dosage
of CPK and aldolase may be slightly more sensitive than the sole dosage of
CPK.10 In the particular case of skeletal myopathy associated with myocardial
involvement, muscle enzymes are very elevated in almost all cases (90–100%).
In addition, 80–100% of these patients also have an elevated fraction of the
MB isoenzyme of CK.13,18 Accordingly, even if not specifically documented in
SSc patients with skeletal myopathy (the reference studies being too ancient),
the troponin level would certainly be elevated in such situations.
EMG examination is abnormal in the vast majority of cases. These abnor-
malities are similar to those evidenced in idiopathic inflammatory myopathies,
that is, shorten mean potential duration, increase in polyphasic potentials,14
fibrillation, positive sharp waves, and repetitive discharges.24

AUTOANTIBODIES

Among all autoantibodies possibly associated with SSc, anti-PM/Scl have

been specifically associated with myositis. These antibodies recognize a
nucleolar complex that is the human counterpart of yeast exosome, a com-
plex consisting of 11 exoribonucleases involved in degradation and process-
ing of different RNA species.31 The main autoantigenic proteins are PM/Scl-
100 and the long PM/Scl-75 isoform.32 Among patients with myositis and
SSc, anti-PM/SCl antibodies are encountered with very diverse frequencies
(10–83%).29,32–35 Conversely, SSc patients with positive anti-PM/Scl antibod-
ies display 43–58% of myositis, these prevalences being significantly higher
as compared to PM/Scl-negative SSc patients in two studies.29,36 Most of
these patients (80–100%) present the limited cutaneous form of SSc, with a
high frequency of calcinosis (10–38%) and usual visceral SSc involvements
(esophagus, lung, heart, etc.). The muscle involvement is characterized by a
mild weakness, a mild CPK elevation, and a mild inflammatory myopathy
at muscle biopsy, fulfilling the criteria of polymyositis or dermatomyositis by
Bohan and Peters.34,35 Unfortunately, immmunopathological characteristics of
276 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES

patients with anti-PM/Scl antibodies have not been studied so far. In a dermato-
logic series, 25% of patients display DM-like skin changes, that is, periorbital
erythema, Gottron’s sign, or papule,34 and another study reported 26% patients
with “mechanistic’s hands” (without associated antisynthetase antibodies).35
Positivity of antiPM/Scl antibodies was linked to HLA-DR3 serologic typing
in both studies. The term “scleromyositis” has been proposed to characterize
this myositis/scleroderma overlap. Nevertheless, one must stress that PM/Scl
antibodies are not specific for this syndrome because they are present in 3–
10% of SSc patients without myopathy29,32,35,36 and in 5–8% of patients with
myositis without SSc.35,37 There is a practical interest in individualizing this
PM/Scl scleromyositis entity because it is reported to respond very well to
mild doses of corticosteroids (not more than 10 mg per day), although some
severe courses have also been described.
Another controversial entity is the so-called “mixed connective tissue dis-
ease” (MCTD), which shares clinical features with several other connective
tissue diseases: rheumatoid arthritis, Sjögren’s syndrome, SSc, and to a lesser
extent systemic lupus erythematosus. MCTD is associated with anti-U1RNP
antibodies. Since the initial description of Sharp, several diagnosis criteria
have been proposed, with a constant requirement of anti-U1RNP antibodies
and diverse clinical criteria, such as edema of hands, synovitis, biopsy-proven
myositis, Raynaud’s phenomenon, and acrocyanosis.38 Nevertheless the ex-
istence of MCTD as a separate connective disease has long been and is still
questioned.39 Indeed, after a long follow-up, more than 60% of MCTD patients
evolve toward a definite autoimmune rheumatic disease, in particular SSc in
20–30% of cases. In addition, anti-U1RNP antibodies are also found in several
other autoimmune diseases, including systemic lupus erythematosus, Sjögren’s
syndrome, and SSc. Twenty to 75% of MCTD patients present inflammatory
myopathy at diagnosis, but muscle involvement remains an important concern
in only 5% of them during follow-up because it responds very well to low-dose
corticosteroids.40 In the case of definite SSc, the individualization of patients
with anti-RNP antibodies (0–20% according to the series21,29,41,42 ) may be
supported by their association with a better prognosis,29,42 but their labeling
as MCTD is probably not justified.39 In these SSc patients with anti-RNP
antibodies, an inflammatory myopathy is more frequently identified than in
other SSc patients, except when compared to PM/Scl-positive patients (27%
if anti-RNP antibodies positive versus 58% if anti-PM/Scl positive).29

MYOPATHOLOGICAL CHARACTERISTICS

Muscle histological findings are heterogeneous in SSc-associated myopa-

thy and include typical features of inflammatory myopathy, together with SSc-
specific features, in various proportions. Most of pathological studies available
in the literature included SSc patients who underwent quadriceps or deltoid
RANQUE et al. 277

biopsies, which were performed either in consecutive patients, whatever the

muscular clinical or biological findings,11,43,44 or only in SSc patients who pre-
sented muscle weakness.15,24 Muscle tissue injuries in SSc mainly include (a)
endomysial microangiopathy, (b) interstitial fibrosis, and (c) inflammation. As
stressed by Engel and Hohfeld,45 two main patterns of muscle involvement are
observed (FIG. 1). First, in most SSc patients, muscle biopsy usually discloses
perimysial fibrosis with or without perimysial inflammation, microangiopathy,
and type 2 fiber atrophy, but little if any myofiber destruction. In a smaller
proportion of patients, muscle involvement appears more severe and com-
bines features of scleroderma with full-blown inflammatory myopathy, either
polymyositis or dermatomyositis, with significant myofiber injury and necro-
sis. The specific histopathological features mainly consist in microangiopathy,
which may be observed in 044 to 57% of the cases,10,24 that is, rarefaction of
capillaries, capillary wall thickening, endothelial proliferation, and thickening
and lamination of the basement membrane upon electron microscopic examina-
tion.11,24 These muscle microvascular abnormalities, particularly the increased
capillary diameter and basal membrane thickness15 and the decreased number
of capillary per muscle fiber43 have been shown to be significantly more fre-
quent in SSc patients as compared to patients with other rheumatic diseases
(polymyositis, rheumatoid arthritis). An increased fibrosis can also be observed
in the perimysium and epimysium, which appears to be much more frequently
identified in autopsy series (93% in Medgser et al.10 ) than in living patients
(25–50%11,24 ). Whether fibrosis is the consequence of vasculopathy-induced
hypoxia and necrosis or of inflammation or both remains to be clarified. In addi-
tion, less specific features such as variation in muscle fiber size and shape, type
II muscle fiber atrophy, and perivascular or perimysial mononuclear cell infil-
trate (43–63%) are frequently encountered.10,20,24 In cases with conspicuous
inflammation, infiltrates are mostly composed of mononuclear cells (lympho-
cytes, monocytes, macrophages), and more prominent in perivascular area.10,20
Extensive immune characterization of this inflammatory infiltrate has hardly
ever been reported in the literature. One study showed that inflammatory cells
in SSc-related myopathy were predominantly CD8+ T lymphocytes, with lower
levels of CD4+ cells, few B cells, and no complement deposits, consistent with
a cell-mediated immune response,46 as observed in polymyositis. Conversely,
in several patients the immunopathological pattern observed is similar to that
encountered in dermatomyositis, with a majority of CD4+ T cells and B cells,
and complement deposits on vascular walls, therefore rather evocative of hu-
moral immune process, suggesting that endothelial injury and intimal prolifer-
ation may be mediated by complement-fixing antibodies.47 Further studies are
needed to better characterize histopathological characteristics of SSc-related
myopathy. In particular, more significant progresses could be provided by sys-
tematic use of immunohistochemical techniques allowing accurate delineation
of muscular immunopathological processes, and computerized morphometry
allowing analysis of endomysial microvascular bed.
278 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
RANQUE et al. 279

PROGNOSIS AND TREATMENT

In the study of Clements et al. that was mentioned in the classification

section,12 two distinct presentations could be isolated, which were associated
with different courses of the muscular disease. The patients with “complicated
myopathies” had an acute and severe muscle involvement upon clinical presen-
tation, high levels of serum CPK, and important EMG abnormalities, and 3 of
4 had an excellent response to corticosteroids. On the opposite, the 19 patients
with more discrete presentation had a spontaneous stable course of muscle
disease. Nevertheless, such a binary classification was not confirmed in other
studies10,11,18,24 and in our experience, clinical evolution cannot be predicted by
the sole initial clinicobiological presentation. Nevertheless, a possible predic-
tion of the response to corticosteroid treatment on the basis of muscle pathology
is worth being considered. Indeed, although very few histological data were
available in Clements et al. series,12 it is remarkable that all muscle biopsies
of “simple” myopathies and the biopsy of the fourth “complicated myopathy”
(that only partially respond to corticosteroids) showed no sign of inflammation.
Conversely, the biopsies performed in the first three “complicated” myopathies
that responded very well to steroids revealed an inflammatory myopathy. A few
other cases of histopathology-proven inflammatory myopathies, described as
similar to polymyositis (again with all restrictions of nonimmunopathologi-
cal studies), were reported to respond to high-dose corticosteroids.13,17 Other
immunological treatments have never been assessed in the particular setting
of SSc-associated myopathy. This differentiation between inflammatory and
noninflammatory myopathy is actually nonredundant with the “simple” and
“complicated” classification. Indeed, even though patients with inflammatory
myopathies are prone to display higher levels of serum CPK and more severe
motor deficit, some of them could have mild clinical symptoms and no CPK
elevation. Conversely, some patients with a clinically “complicated myopathy”

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
FIGURE 1. Histopathological features in SSc-associated myopathy: muscle biopsy
showing myofiber injury (A–C), interstitial fibrosis (D–F), and microangiopathy (G–K).
(A) Severe muscle involvement with necrosis and atrophy of muscle fibers, extensive fibro-
sis, and perimysial inflammation (hematein-eosin, HE); (B) CD56/N-CAM immunostain-
ing showing numerous scattered regenerating fibers (immunoperoxidase); (C) major histo-
compatibility complex-class I immunostaining showing heterogeneous pattern of myofiber
re-expression (immunoperoxidase); (D) Masson’s trichrome staining showing collagen de-
position (azure blue) witnessing interstitial fibrosis; (E–F) loss of fibroblast in sclerotic
interstitium (E: HE; F: CD34, immunoperoxidase). Endomysial microangiopathy assessed
by lumen dilatation (G, arrow; H, arrows; J), capillary wall thickening (G, arrowheads),
membrane attack complex deposition (I), and capillary loss (K) (G: HE; H: smooth mus-
cle actin [pericytes], I: C5b-9, J and K: CD31 [endothelium], immunoperoxidase). Light
microscopy, frozen sections. (In color in Annals online.)
280 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES

may correspond, upon pathological examination, to noninflammatory muscle

disorders that do not improve under corticosteroids.18,24
To conclude, because patients with no documented inflammatory myopathy
seem to evolve very slowly or to remain stable in the absence of specific treat-
ment, and because patients with dSSc are highly susceptible to renal crisis, we
propose to restrict high-dose corticosteroid treatment to patients with histo-
logically proven inflammatory myopathies only. A prognostic study assessing
the interest of muscle pathology in response to treatment is ongoing to validate
this proposition.

ACKNOWLEDGMENTS

Alice Berezne, Loı̈c Guillevin, and Luc Mouthon are members of the Groupe
Français de Recherche sur la Sclérodermie.

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