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Skeletal muscle involvement in progressive systemic sclerosis scleroderma.

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Skeletal Muscle Involvement in
Progressive Systemic Sclerosis (Scleroderma)
By THOMAS
A. MEDSGER,
JR., GERALD
P. RODNAN,
JOHN M o o s s ~
AND JOHN W. VESTER
53 patients with typical PSS were examined for evidence of muscle weakness,
abnormal serum enzymes, disturbances
in urinary creatine and creatinine, and
histopathologic alterations in skeletal
muscle tissue. The majority was found
to have clinical and biochemical features
C
of primary myopathy. Microscopic involvement of muscle fibers or interstitium was present in 14 of 36 cases;
the most consistent abnormality was
interstitial fibrosis. This muscle involvement is considered an important feature
in the course of PSS.
involvement of skeletal muscle
in progressive systemic sclerosis
(PSS) was described in 1876 by Westphal,
who noted severe shoulder girdle atrophy
in a woman with scleroderma and suggested that a primary myopathy was responsible.’ In 1895, Lewin and Heller
reviewed reports of 26 cases of muscle
atrophy in this disease.2 These authors, together with Dinkler3 and MCry,4 observed
an increase in connective tissue as the dominant microscopic change, although some
muscle fiber degeneration was also present.
Frequent case reports since that time have
confirmed these findings, although it is
likely that many of the patients would be
classified today as dermatomyositis with
skin changes suggestive of PSS.5-12
Brock presented 3 cases illustrating the
diagnostic dilemma created when PSS
mimics dermatomyositis, and showed that
myopathy in the former was not necessarily
associated with involvement of directly
overlying skin.13 More recently, Tuffanelli
and Winklemann have used the term “sclerodermatomyositis” in describing 36 patients
in whom muscle disease so dominated the
clinical picture that distinguishing between
scleroderma and dermatomyositis was imp0ssib1e.l~ Striated muscle abnormalities
have also been found in other diseases
which clinically overlap PSS. Adams and
co-workers described “interstitial nodular
polymyositis” in scleroderma; they believe
this finding cannot be differentiated microscopically from that seen in rheumatoid
arthritis (RA) and systemic lupus erythematosus ( SLE).15 Desmarais et al. called attention to the frequency of histological abnormalities in muscle tissue of patients with
From the Departments of Medicine and Pathology, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania 1521 3.
This stu& was supported by a Graduate Training Grant in Arthritis and Rheumatism (2A-5031)
USPHS Grant 5-M01-FR-00056, and a grant from
the Western Pennsylvania Chapter, Arthritis
Foundation.
THOMAS
A. MEDSGER,JR., M.D.: Trainee in
Rheumatic Diseases, Department of Medicine,
University of Pittsburgh, Pittsburgh, Pennsylvania.
GERALDP. RODNAN, M.D.: Professor of Medicine,
University of Pittsburgh. JOHN M o o s s ~ , M.D.:
Present address: Professor of Pathology, Bowman
Gray School of Medicine, Winston-Salem, North
Carolina. JOHN W. VESTER, M.D.: Associate Professor of Medicine, University of Pittsburgh, and
Associate Chief of Staf, Oakland V. A. Hospital,
Pittsburgh. Present address: Department of Research, Good Samaritan Hospital, Cincinnati, Ohio.
554
LINICAL
ARTHRITIS
AND RHEUMATISM,VOL. 11, No. 4 (AUGUST
1968)
555
SKELETAL MUSCLE INVOLVEMENT IN PSS
RA,l6 and Pitkeathly and Coomes have recently described 3 cases of RA with polymyositis, in which serum enzyme and
biopsy alterations were indistinguishable
from those in polymyositis alone.'? Numerous accounts have indicated that untreated
SLE may be associated with prominent
myositis.ls
Although there is general agreement that
there may be conspicuous muscle wasting
in severe scleroderma, the documented
prevalence of skeletal muscle involvement
in PSS has varied widely in published reports. Pearsonl9 has pointed out, however,
that pathologic alterations are common in
muscle biopsies from individuals with
chronic disease states, and that these nonspecific lesions may well contribute to clinically observed muscle atrophy and weakness. To what extent the changes in PSS
result from disuse atrophy and to what extent they represent primary myopathy has
not been determined. In the present study,
53 patients with typical PSS were evaluated
with respect to clinical, pathological, and
biochemical features of skeletal muscle disease. The majority of these individuals was
found to have evidence of a primary myopathy .
MATERIALS
AND METHODS
Subjects
The patients chosen for this study were designated as having PSS on the basis of two chief
criteria: 1) Raynaud's phenomenon and/or typical
sclerodermatous skin changes; and 2) involvement
of the gastrointestinal tract documented by abnormal distal esophageal motility at fluoroscopy
and/or classical radiographic small bowel or colon
changes.
Other evidence of systemic involvement in this
group included arthritis, pulmonary fibrosis, and
myocardial and renal disease typical of PSS. Ten
patients are included who have Raynaud's phenomenon and extensive, diffuse dermal changes
without demonstrable alimentary tract lesions;
they have been followed for 2 to 12 years. Although we have encountered several patients who
present combinations of features of scleroderma,
SLE, RA, and dermatomyositis, these have been
purposely excluded in order to limit the series
as nearly as possible to classical PSS. The final
list consists of 33 patients under current observation (Table 1, patients 1-33), 5 individuals who
died during the period of the study (September,
196SJanuary, 1967) (patients 34-38), and 15
others followed at this center during the period
1955-65 who had autopsy samples of striated muscle available for review (patients 39-53 in Table
1). There were 20 men and 33 women, ranging
from 17-75 years in age, who had clinical evidence of scleroderma for 1 3 1 years.
Clinical Evaluation
Weight loss was determined from each patient's
weight at the time of study compared to his
started weight prior to the onset of symptoms of
scleroderma (including Raynaud's phenomenon).
Individuals were carefully questioned regarding
symptoms referable to myopathy, the interviewer
attempting to separate those complaints of articular origin. Muscle groups were tested in the standard fashion (normal, good, fair, poor, trace, zero)
described by Daniels, Williams, and Worthington.20 Thirty-eight patients were so examined; the
remaining 15 were evaluated on the basis of previously recorded physical examinations. The muscles tested were those of the hip and shoulder
girdles, and the muscle groups of the arm, forearm, hand, thigh, leg and foot. Combined judgments were made for proximal and distal
musculature of both upper and lower extremities,
and then a single rating was made for each patient,
designed as an overall clinical estimation of muscle weakness. Atrophy of muscle groups, which
was present in variable degree, was not included
in this evaluation.
Serum Enzymes
Determinations of creatine phosphokinase
(CPK), aldolase, lactic dehydrogenase (LDH), and
glutamic oxalo-acetic transaminase ( SGOT ) were
made on the fresh sera of 35 patients; LDH and
SGOT values were included from the past records
of 9 other individuals. CPK was determined by a
modification of the method of Noda et a1.21 The
normal range has been found to be 0-1.5 micromoles of phosphate/ml. serum/hr.*1-23 These
units can be converted to International Units by
multiplying by a factor of 16.6. Aldolase, measured by spectrophotometric assay originally described by Bruns, ranges from 0.9-2.5 milliunits/
ml. serum.21 The upper limit of normal in this
study was taken as 3.0 milliunits. SGOT (0-45
Table l.--Clinical, Biochemical, and Histological Findings Relative t o Skeletal
Muscle Involvement i n 53 Patients with Progressive Systemic Sclerosis
Dogre of
Age, sex
Disease %Lnss
duration
in
(yrs.) body wt.
33. I.L.
57-F
48-F
60--hI
61
24--F
24
49-hI
63-hf
75-F
62-F
62-F
53-F
53
37-F
70-M
59-F
47-M
49--F
27-F
28
17-F
20
36-ni
49-M
48-M
60-F
37-F
37
41
48-F
57-F
46-F
46-F
53-M
66-M
57-M
49-F
45-hI
55--M
40-F
31
39
8
13
2
15
3
20
3
17
3
27
4
7
0
10
29
6
2
6
0
10
3
0
3
4
3
0
8
20
12
35
2
18
3
3
2
0
3
2
4
2
7
2
18
1
24
2
5
12
2
15
0
16
16
0
2 0 7
12
0
13
26
2
0
5
0
7
22
2
0
10
8
4
0
18
10
17
3
4
29
34. IS.
57-F
20
23
29
1
1
13
3
20
22
6
7
30
++
++
++++
3
4
23
0
16
+++
++
Patient
1. A.K.
2. E.P.
3. W.D.
4. S.B.
5.
6.
7.
8.
9.
10.
G.W.
M.A.
E.H.
H.H.
S.T.
E.B.
11. D.P.
12. J.H.
13. B.G.
14. J.F.
15. R.P.
16. B.C.
17. M.C.
18.
19.
20.
21.
22.
R.L.
J.H.
C.W.
A.P.
A.Y.
23.
24.
25.
26.
27.
G.R.
M.K.
E.B.
D.McV.
L.E.
28. A.E.
29.
30.
31.
32.
G.B.
M.B.
J.S.
J.T.
60
35.
36.
37.
38.
A.R.
M.B.
P.S.
C.P.
39. E.V.
40. M.W.
il. L.0”.
66-F
65-41
3&F
53-F
46-F
44-F
48--M
1
muscle
weakness
(summary)
++++
++
+++
+++
++
++++
++
-
++
++
+
+++
+++
+++
+
++++
++++
++
+
+++.
+
+
+
+++
++
++
+
+++
++
++
+
++
++
+
+++
++++
++
*Based on “creatinine coefficient”24.
tI3 = biopsy specimen; A = autopsy specimen.
Urinary
creatinine
(Gm./24 h,
Actual R Prcd.’
0.52
0.77
0.63
1.01
1.07
0.71
1.29
1.57
0.80
0.79
0.96
0.87
0.84
1.19
0.61
0.47
1.48
1.00
0.79
0.86
0.63
0.42
0.53
0.46
1.14
0.72
1.00
0.83
0.45
0.78
0.49
0.71
0.80
1.01
1.03
0.73
0.73
1.67
0.90
0.65
82
102
45
78
82
79
74
90
71
93
63
105
106
82
58
107
127
87
92
93
77
54
31
39
82
75
95
89
50
106
68
94
74
70
59
53
47
91
75
86
1.04
0.60
0.43
Histopathologic abnormalities
Inlerstitium
Conn.
a@e;.
hluscle Muscle tissue Blood
mg./24 h. (milliunits/ml.) snurcet fiber and fat vessels
165
47
48
98
74
259
34
55
77
142
24
184
179
110
45
255
61 1
44
34
51
2
65
8
20
51
42
29
55
49
237
44
134
44
102
R
+
+
+
B
B
-
+
+
B
-
-
-
B
B
-
-
-
B
-
-
-
R
-
-
-
62
81
144
4.09
2.95
4.50
1.93
3.14
3.00
3.04
2.39
3.40
5.10
3.70
B
-
-
-
80
61
75
43
355
2.44
6.13
0.77
0.43
74
47
100
:I
A
A
B
A
+
+
+
+
+
+
+
+
+
+
+
+
0.56
0.56
1.34
77
62
84
270
88
30
A
A
+
+
+
-
4.13
2.50
3.72
7.40
12.00
2.20
2.45
2.35
2.72
2.70
3.65
3.22
3.40
3.07
2.12
3.22
2.29
-
2.56
3.29
2.80
3.60
4.50
2.84
-
-
-
SKELETAL hfUSCLE INVOLVE-NT
Patient
Age. sex
50
42. A.A.
43. W.R.
44. n1.c.
45.
46.
42.
48.
49.
50.
51.
52.
53.
A.J.
B.S.
R.M.
S.C.
H.G.
I.K.
W.W.
.J.S.
R.V.
51
38-A1
43--;\I
45
54-1;
55
63-1:
42-F
32-11
41-1:
71-F
35-F
4541
53--RI
36--hI
Disease %,Loss
duration
in
(yrs.) body wt.
3
4
1
1
3
2
2
3
6
3
2
1
5
2
1
4
21
21
15
5
5
9
11
38
18
0
4
5
8
4
13
14
557
IN PSS
Degree of
muscle
weakness
(summary)
+++
+++
++++
+
+
+
+
++
++
++
Histopathologic abnormalities
Interstitium
Urinarv
creatinihe
urinary
SCNm
Conn.
(Gm.124 h)
creatine
aldolase
Muscle Muscle tissue Blood
Actual % Pred.’ mg./24 h. (milliunits/ml.) sourcet fiber and fat v e ~ ~ e l s
1.03
0.90
1.29
1.17
0.95
0.73
0.56
+
++
++
units/ml. serum)23 and LDH (100550 units/ml.
serum)26 were determined by standard methods.
Urine Creatine and Crcatinine
Twenty-four hour urine samples were collected
from 43 patients; 3 or more consecutive specimens were obtained in all but 6 cases. Most of
these persons were in-patients on balanced, low
protein, meat-free diet which was begun 48 hours
prior to the first collection. Samples of volume
less than 1000 cc. and those from patients with
renal failure and elevated serum creatinine levels
were omitted. Five patients (patients 14, 23, 42,
46, and 50 in Table 1) were taking corticosteroids
(prednisone, 10 mg. or less per day) at the time of
the collections, and one (No. 24) was receiving
weekly intramuscular ACTH. Potassium aminobenzoate, epsilonaminocaproic acid, cortico-teroids,
low molecular weight dextrans, and chloroquine
were given for varying periods of time to others,
but no reported data were obtained while these
agents were being used. Urinary creatine and
creatinine were determined by the method of
MacFate et al.27 Opinion varies about normal
daily creatine excretion; in this study we used
0-50 mg. for men and 0-100 mg. for women.
Creatinine is relatively constant at 20-26 mg./Kg.
body weight for males and 14-22 mg./Kg. for
females. The “creatinine coe5cient,” as described
by Shaffer, was calculated by adding urinary
creatine and creatinine, and expressing this value
in mg./Kg. body weight.28 The percentage of predicted creatinine coefficient (Table 1) was determined by coinparison of the actual and predicted
67
59
99
71
45
72
56
24
105
5
-
+
A
A
+
+
-
A
+
+
-
A
A
A
A
A
A
A
A
A
A
+
+
-
+
+
-
-
-
-
-
-
-
coefficients (predicted based on 25 mg./Kg. for
males and 20 mg./Kg. for females). In 6 patients,
creatine excretion values were not available.
Pathologic Materid
Skeletal muscle was obtained in 36 cases, consisting of 18 open biopsies, (one case, patient No.
1, was biopsied in 2 areas, deltoid and gluteus),
and 19 post-mortem specimens. Fifteen of the 18
biopsies were taken from the deltoid; no attempt
was made to sample those muscle groups showing
the most severe weakness or tenderness. Of the
autopsied cases, only the 5 examined during the
course of the study (patients 34-38) had multiple
specimens available for review. The earlier postmortem materials frequently contained only 2 muscle samples, diaphragm and deltoid. All available
autopsy samples were studied, including intercostal, diaphragm, rectus abdominis, tongue, anterior
tibial, quadriceps femoris, and pectoral muscles.
Sections were routinely fixed in 10 per cent formalin, embedded in para5n, and stained with
hematoxylin and eosin; in some cases trichrome
(Mallory and Masson) stains were done. Four biopsy specimens were fixed with 1 per cent osmium
tetroxide and 5 per cent glutaraldehyde followed
by 1 per cent osmium tetroxide, and prepared for
electron microscopy. Microscopic diagnoses were
made at two separate sittings without knowledge
of the clinical features. In only 2 cases was there
a difference in interpretation recorded, and in no
case was a frankly abnormal diagnosis altered to
normal or vice-versa. Pathologic changes were
classified under the broad categories of muscle
558
MEDSGER, RODNAN, MOOSSY, WTER
Fig. 1.-Extensive peri- and epimysial fibrosis in cross section in deltoid muscle;
fibrosis mixed with scattered chronic inflammatory cells. Muscle fibers distorted
and some with central nuclei. (Case No. 1) Hematoxylin and eosin, 2 7 0 ~ .
fiber and interstitial tissue alterations, the latter
being subdivided into lesions of connective tissue
and fat and those of blood vessels.
A word of caution in the interpretation of muscle biopsies has been raised by Engel, who points
out that certain focal myopathic changes can be
produced by electromyographic and hypodermic
needles.29 That this is important in patients with
chronic diseases such as PSS should be apparent
when one considers the frequency with which the
deltoid and gluteal areas are used for the injection
of steroids and other drugs. We were aware of
this possibility in our interpretations of the histopathologic features in these patients; no focal
changes in the deltoid or gluteal muscles were
described which had not also been detected in
the quadriceps, anterior tibial, or other muscle
groups.
RESULTS( TABLE
1)
Clinical Evaluation
The average weight loss after onset of
PSS was 12 per cent. Over 60 per cent of
the patients were aware of easy fatigability
and weakness, but those symptoms were
usually poorly localized. Although marked
weight loss (greater than 20 per cent body
weight in 14 patients) and severe to
marked objective muscle weakness (16 patients) were noted frequently, only 7 individuals presented specific symptoms related to muscle involvement. Six of these
complained of generalized muscle aching
and one of “cramps”; in only 2 was there
evidence of muscle tenderness. Typically
there was more marked weakness of the
proximal muscle groups, especially the pectoral girdle, which was involved to some
extent in 20 of 38 patients carefully examined. Forearm flexors and extensors and the
intrinsic hand muscles were more commonly affected (26 of 38), but the most extensive dermal and articular changes were
in proximity to these muscles. Loss of
muscle mass was often seen around joints
with synovial involvement, primarily knees,
ankles, elbows, wrists, and MCP and PIP
SKELETAL MUSCLE INVOLVEMENT IN PSS
559
Fig. 2.-Fibrosis, muscle fiber atrophy and abortive regeneration in longitudinal
section in quadriceps muscle. (Case No. 35) Hematoxylin and eosin, 270 x .
Urine Creatine and Creatinine
The average creatine excretion for the
entire group (38 patients, 234 urine specimens) was 110 mg.124 hours. 58 per cent
(8 of 14 men and 14 of 24 women) showed
clearly elevated values at some stage in
their clinical course, ranging as high as
611 mg.124 hours (patient 14). At the time
of most recent examination, the average
daily urinary creatinine was 0.817 Gm.
When compared with their predicted excretion of creatinine, plus creatine, calcuSerum Enzymes
lated as creatinine coefficient, most patients
CPK levels were normal in all but 3 pa- produced subnormal amounts, ranging from
tients, who showed mild elevations (1.80- 31-127 per cent and averaging 74 per cent
2.50 units). LDH and SGOT were raised of predicted values. In 10 instances, pain only one instance (case No. 4) and this tients were re-evaluated after an interval
woman displayed elevation of all enzymes. of 6 months or longer; 6 of these showed
The most common abnormality was aldo- significant decreases in urinary creatinine
lase activity, which was high in 20 of 35 in- excretion over time (patients 17, 22, 34, 41,
stances, and ranged as high as 12 milli- 43, 44), indicating disproportionate loss of
units/ml. serum (again, case No. 4).
muscle mass.
joints of the hands. The shoulder girdle,
however, was frequently atrophic and weak
without evidence of articular disease. Clinical estimation of the degree of muscle
weakness revealed the following distribution:
none
10 patients
9
minimal (+)
moderate (++) 18
severe (+++) 10
marked(++++) 6
560
MEDSGER, RODNAN, MOOSSY, VESTER
Fig. 3.-Interstitial collection of lymphocytes in
quadriceps. (Case No. 35)
Hematoxylin
270 x .
and
eosin,
Pathologic Findings
No gross abnormality of the freshly obtained muscle was found. Significant histological abnormalities were noted in skeletal
muscle from 14 of 36 patients. These alterations occurred more often in tissue obtained at autopsy (10 of 19) than by biopsy
( 4 of 17). The muscles most commonly affected were those most often sampled at
autopsy (deltoid, pectoral, forearm groups,
and diaphragm) but tongue and anterior
tibia1 musculature occasionally showed histopathologic changes. These lesions appeared to be independent of overlying dermal thickening. In 3 instances deltoid biopsies were normal despite considerable
involvement of the skin of the upper arm
(patients 3,4, and 14).
The most common change was interstitial and perivascular fibrosis ( 13 cases),
followed in frequency by interstitial and
perivascular inflammatory infiltrates (8
cases) and myofibril atrophy, necrosis, and
degeneration (10 cases). It was unusual to
see muscle fiber lesions without interstitial
reaction, and vice-versa. However, skip
areas, in which these two processes were
spatially separated, were often present in
the same muscle specimen.
A wide spectrum of muscle fiber abnormalities was found, including atrophy,
necrosis, and eosinophilic floccular degeneration. A few cases showed patchy foci
in which muscle fibers were intensely necrotic, with abundant nuclear debris, obliteration of the usual myofibrilIar Iandmarks,
and little or no adjacent inflammatory reaction. Changes in the interstitial tissue
were characterized chiefly by irregularly
distributed islands of peri- and epimysial
fibrosis (Figs. 1 and 2) and increased interstitial fat. These lesions occurred both
SKELETAL MUSCLE INVOLVEMENT I N PSS
Fig. 4.-Perivascular
561
fibrosis. (Case No. 41) Hematoxylin and eosin, 270 x .
DISCUSSION
early and late in the clinicalcourseof
PSS. Scattered cellular infiltrates (mainly Clinical Evaluation
lymphocytes with occasional plasma cells
Evaluation of muscle strength is particuand, more rarely, neutrophilic leucocytes )
larly
difficult in the presence of articular
were most often located in the interstitiurn
disease,
and atrophy in such circumstances
(Fig. 3), and in only 2 instances were
these aggregates distinctly nodular in ap- may not reflect primary myopathy. In fact,
pearance. Perivascular inflammatory infil- it was our impression that a considerable
trates were present in 3 cases. Perivascular portion of muscle wasting in these patients
and perineural fibrosis were seen in vary- with PSS was the result of disuse. Furthering degrees, usually mild, in 5 specimens more, other more ominous features of
(Figs. 4 and 5). Fibrinoid degeneration, as scleroderma leading to general debility also
illustrated in the perineural connective tis- contributed to loss of muscle mass. Malabsue in Fig. 5, was noticed only once. No sorption, renal failure, and congestive heart
primary vascular inflammation was seen in failure due to myocardial and/or pulmonary
this material, in the sense of a cellular in- fibrosis thus resulted in atrophy out of profiltration of blood vessel walls. In one case, portion to objective evidence of active
vessel wall calcification was present in the muscle cell injury.
We were impressed by the frequency
anterior tibia1 musculature, but it was not
possible to determine the exact type of ves- with which severe muscle atrophy and 011sel from the sections available. Electron jectively measured weakness were found
microscopic examination of 4 specimens despite an absence of specific complaints.
failed to reveal any significant alteration in The muscle disease in these patients was
usually insidious, in contrast to the more
capillaries or myofibrils.
MEDSGER, RODNAN, MOOSSY, VESTER
562
Fig. 5.-Perineural fibrosis with fibrinoid alteration in connective tissue. (Case
No. 41) Hematoxylin and eosin, 270 x .
acute exacerbations characteristic of dermatomyositis. Both diseases preferentially
involve proximal musculature, but in PSS
the muscles of the forearms and hands are
frequently affected, together with adjacent
skin and joints. Only 12 individuals showed
completely normal distal upper extremity
function, and in these acral skin changes
were minimal or Raynaud's phenomenon
alone was present. More akin to dermatomyositis was the frequent shoulder girdle
weakness, which was most often unassociated with articular or para-articular disorders.
Urine Creatine and Creatinine
Under normal conditions, 2 per cent of
muscle creatine is hydrolyzed and excreted
daily as creatinine. The amount of urinary
creatinine has long been recognized as a
reflection of body creatine stores, and is
thus considered a measure of body muscle
mass. Christianson et al., in their discussion
of polymyositis, reported 11 cases of scleroderma with an average daily creatinine excretion of 857 mg., far below their figures
for patients with other diseases not usually
. ~ ~ also obassociated with m y ~ p a t h y We
served a low average daily urine creatinine
of 817 mg.; however, there was no correlation between the decrease in creatinine
and degree of muscle weakness for each
patient. The 6 patients considered to have
the most marked functional impairment of
muscle (patients 1, 4, 17, 35, 38, and 42)
excreted close to the average weight-based
predicted amounts of creatinine. On the
other hand, 6 of 10 restudied after intervals of 6 months or more did show disease
progression, increasing muscle weakness,
and concomitant decline in the creatinine
output.
It should be cautioned that this index
cannot provide an accurate reflection of
primary myopathy since disuse atrophy
may contribute an important share in the
563
SKELETAL MUSCLE INVOLVEMENT IN PSS
25
t
T
i
WEIGMT LOSS,
% O F NORYAL
BODY WEIGHT
5th
0
8.00
SERUM ALDOLASE 6.00
4.00
Yillirnitr I ml.
m II
1
t
2.00
200
150
URINARY CREATINE
mqml24hn.
100
1
1
-
r-
Fig. 6.-Correlation of degree of muscle weakness with
1 percentage weight loss, serum aldolase level, and urinary creatine excretion. The
figures in parenthesis indicate the number of patients
in each category with respect
3 to muscle weakness. The values represented are the mean
and standard error of the
mean.
-
50 n
CLINICAL ESTIMATION OF DEGREE OF
MUSCLE WEAKNESS
loss of muscle mass. It may, however, be
a rough guide to the severity and rate of
progression of PSS.
Creatine is thought to be synthesized primarily in the liver and stored in voluntary
skeletal muscle, where it exists chiefly as
phosph~creatine.~~
Creatine itself is excreted in large auantities only when muscle
cells are unable to incorporate properly
and/or store pho~phocreatine.~~
In this
study, the average urinary creatine was
107 mg.124 hours, only one-third the average amount found by Christianson et al. in
their patients with s~leroderma.~O
These abnormalities in creatine excretion are less
frequent and more modest in degree than
those found in polymyositis, yet the results
suggest a fair correlation with disease activity. Our 6 patients with marked clinical
myopathy excreted an average of 161 mg.1
day, while those with minimal or no
atrophy or weakness excreted an average of
74 mg./day (Fig. 6). Of the 8 men and 14
women considered to have excessive creatinuria, 16 (73 per cent) were felt to have
active progression of scleroderma, rather
than stable courses, at the time of study.
Fifteen of 19 (79 per cent) with high creutine excretion had aldolase elevations, and
5 of 9 abnormal histopathologic findings.
We found no direct correlation between
creatinuria, decreased urinary creatinine,
and weight loss as Christianson et al.
showed with their dermatomyositis group.
Serum Enzymes
In primary inflammatory and degenerative myopathies, abnormal amounts of many
enzymes are released across sarcolemmal
membranes of injured or dying muscle
cells.33 The high percentage of nldolase
elevations in the present group of patients
with scleroderma was unexpected, especially in view of the low frequency of CPK,
LDH, and SGOT abnormalities. Although
15 to 18 patients (83 per cent) with high
serum aldoIase levels were found to have
creatinuria of excessive degree, only 4 of
10 showed histopathological changes in
muscle. Both aldolase elevation and amount
564
of creatinuria correlated well with the dcgree of muscle weakness (Fig. 6). There
are reports of increased serum aldolase levels in disorders of myometrium and myo~ardium."-~5
Thus it is possible that cardiac
and/or smooth muscle involvement may
contribute to the observed serum aldolase
changes in our patients with PSS.
Pathologic Findings
Surprisingly little has been added to the
exhaustive histological descriptions of Dinkler and M61-y.~.*The frequency of muscle
lesions reported by different observers has
vaned widely. Steiner and Chason found
no changes in 4 patients at autopsy,30
while Piper and Helwig noted abnormalities in all of 25 post-mortem cases?' Morrison and co-workers reported perivascular
lymphocytic infiltrations, mainly endomysial
and perimysial in location, in several patients with PSS.38 LeCoulant and Texier,
in n discussion of 2 cases with pathologic
alterations in muscles far distant from areas
of classic dermal change, emphasized both
severe atrophy of muscle fibers and interstitial dense cellular "nodules" separating
and infiltrating fibers and bundles.39Pende
and DeCarlo stressed the occurrence of myofibril fragmentation and degeneration,
with loss of striations, eosinophilic homogenization, and sarcolemmal nuclear prolifera t i ~ n . ~ "Infiltrative changes were less
prominent in their cases, but areas of fibrosis appeared in all 8 samples studied. The
striated muscle changes in PSS, although
similar in quality to those of other connective tissue disorders, were felt by Walton and Adams to be characterized primarily by increase in interstitial connective
tissue with fibrosis.41
Of the total of 36 patients in this series
with tissue specimens available, one would
have predicted from clinical and/or laboratory findings that 26 would show some
histologic changes in skeletal muscle; how-
MEDSGER, RODNAN, MOOSSY, VESTER
ever, as previously noted, only 14 were
abnormal. The most striking discrepancy
was in the low yield of biopsy changes
( 4 of 17) . This difference may be explainecl
by 2 factors: 1) Those individuals who
succumb to PSS have more serious disease;
thus autopsy material would be expected
to have more histopathologic abnormalities;
and 2) The single muscle biopsy has limited
reliability. Thirteen of these biopsied patients had moderate to severe muscle weakness, and of 15 completely studied, 12 had
elevated serum aldolase values and 9
showed excessive urinary creatine. These
findings support the concept that a single
muscle specimen is frequently not histologically representative.
Electron microscope evaluation of ultrastructural abnormalities in skeletal muscle
(abductor pollicis brevis and brachioradialis) from 2 patients with PSS has been
reported by Michalowski and K~dejko.*~
Decreased numbers of mitochondria, their
vacuolization, and granular degeneration,
and vascular changes including capillary
wall thickening and lumen obliteration
were described. Norton, Hurd, and Ziff
found abnormal capillary ultrastructure in
studying quadriceps muscles from scleroderma patients.43 We have processed 4
specimens for electron microscopy, but no
conclusive changes could be demonstrated
in capillaries or myofibrils when compared
with control material.
The frequency of elevated aldolase levels
and creatinuria in this group of patients
with PSS confirms that in most instances
muscle cell degeneration is occurring.
These findings correlate well with clinical
evidence of muscle weakness and loss of
muscle mass (Fig. 6), and we believe that,
taken in the aggregate, they are a more
reliable index of muscle disease than the
results of an isolated muscle biopsy.
Quantitatively, the frequency of lesions
found in PSS (39 per cent) in this study
565
SKELFTAL MUSCLE INVOLVEMENT I N PSS
is in keeping with 45 per cent reported by
C r ~ i c k s h a n kin~ ~“rheumatic diseases” and
34 per cent by Sokoloff et a l j 5 in 202
cases, 57 of which were rheumatoid arthritis. It should be noted that we had available for study only 2 to 4 muscle groups
in the majority of necropsies, compared to
the 7 to 9 sampled by Cruickshank.
We observed muscle lesions in 6 patients
who had little or no weight loss ( 8 per
cent or less of original weight) or general
debility and in 7 individuals who had PSS
3 years or less. Three of the most striking
examples of myositis were patients ill less
than 12 months (patients 32, 34, 50). These
findings emphasize that an important active myopathy is present in PSS, apart from
the changes which can be attributed to
chronic debilitation.
The finding of various combinations of
myofibril and interstitial involvement demonstrated in our patients supports the currently accepted concept that there is no
specific primary muscle lesion in scleroderma. Histopathologic criteria alone could
thus lead to confusion with polymyositis
and other diseases of connective tissue. Accumulations of chronic idammatory cells,
nodular or otherwise, have no recognizable
specificity, and, alone, will not distinguish
PSS, SLE, RA, polymyositis, dermatomyositis and other diseases of connective
tissue.46 Similarly, the vascular lesions, including those associated with fibrinoid
change, have no unequivocal interpretat i ~ n . ~Morphological
?
alterations of the
muscle fiber, formerly given much weight
in other areas of muscle pathology, have
themselves been questioned, even as a
means for distinguishing denervation or
neurogenic atrophy from m y ~ p a t h y . ~ ~
There is one histopathologic feature
which appears more consistently in PSS
than in other diseases affecting connective
tissue. Fibrosis, with increase in interstitial,
perivascular, and perineural connective tissue, is noted by Walton and Adams4’ to be
most frequent in scleroderma and RA. Fibrosis was present in 13 of the 14 abnormal
specimens in our study. Since muscle fiber
degenerative changes and cellular infiltrations are indistinguishable from those of
other disorders, it would be incorrect to
conclude that this fibrosis represents a
unique type of myopathy. Rather it should
be viewed as a type of local response found
more commonly in PSS than in other causes
of myositis.
CASEREPORTS
Case N o . 1 .
A. K. is a 57-year-old woman who developed
Raynaud’s phenomenon in 1936. In 1962, she
noted pain, heat, and swelling of the knees, wrists,
and PIP joints bilaterally. Subsequently there was
tightening of the skin over the fingers, arms, face,
and feet, shortening of the distal phalanges, and
flexion contractures leading to limited mobility of
the hands, elbows, shoulders, and knees. She lost
66 pounds (39 per cent of previous weight) but
did not complain of dysphagia or diarrhea. Painful ulcers appeared over both medial and lateral
malleoli. She was able to feed herself, but required assistance for all other activities; she denied
muscle weakness, tenderness, and cramps.
When admitted to Presbyterian-University Hospital in September, 1965 the patient’s blood pressure was 95/60 mm.Hg and the pulse 88/min.
Her face was “pinched,” with thickened, taut skin
over the nose, cheeks, and neck; similar changes
were noted over the chest, a r m s and hands, and
multiple telangiectatic lesions were present. The
lungs were normal. An apical systolic ejection murmur was present, and the pulmonic component of
the second heart sound was accentuated. There
was no hepato- or splenomegaly. Flexion contractures involved the DIP and MCP joints, wrists,
elbows, shoulders, hips, and knees. Pronounced
tendon rubs were palpable over both knees. There
was profound weakness and wasting of the
shoulder girdle, forearm muscles, and intrinsic
muscles of the hands. The pelvic girdle was also
weak, and marked quadriceps atrophy was evident. She was given an overall rating of
muscle weakness.
The hemoglobin was 10.0 Gm. per cent, hematocrit 33 per cent, WBC 8100/cu.mm. with a
++++
566
normal differential count. The L.E. cell test was
negative. The latex agglutination reaction for
rheumatoid factor was positive in a titer of 1:320.
Total serum protein was 6.8 Gm. per cent with
3.2 Gm. per cent albumin and 1.3 Gm. per cent
gamma globulin. Roentgenographic examination
revealed markedly decreased esophageal motility,
and small bowel hypomotility typical of PSS. Interstitial fibrosis was present on chest x-ray. ECG
was unremarkable.
SGOT was 12, LDH 360, and CPK 1.24. The
serum aldolase was elevated to 4.13 milliunits/
ml. Persistent creutinuriu, averaging 165 mg./24
h, was present on numerous determinations. The
creatinine excretion was 0.52 Gm./24 h, and the
creatinine coefficient was 82 per cent of that predicted for her new weight. Muscle biopsy was
obtained from the deltoid, through definitely
thickened skin of the upper arm. Microscopically
there was irregular myofibril atrophy and necrosis
and some collagenization of muscle fibers. Marked
fibrosis of the interstitium was seen, with increased
fat, and there were scattered lymphocytic infiltrations. (Fig. 1).
Five months later the patient was readmitted
because of pain in the right hip, and found
to have avascular necrosis of the femoral head.
There were no changes in creutine and creatinine
excretion, and aldolase remained the only serum
enzyme elevated. An Austin-Moore prosthesis was
inserted, and at surgery the gluteus medius muscle was biopsied. Muscle fiber degeneration was
present and several areas of calcification were
seen. Interstitial changes were less marked but
similar to those illustrated in Fig. 1.
Case No. 35.
A. R., a housewife, was first examined in 1960,
at age 60, when she complained of a 20-year
history of Raynaud's phenomenon. At that time
she noted arm and shoulder weakness, and tight,
thick, hyperpigmented skin over the fingers, neck,
face, and chest. Blood pressure was 145/95 mm.
Hg, and decreased range of motion of the PIP
and MCP joints was observed. The hemoglobin
was 14.2 Gm. per cent and the hematocrit 43 per
cent, and blood urea nitrogen 8 mg. per cent. The
L.E. cell test was negative. Total protein was 6.5
Gm. per cent with 3.8 Gm. per cent albumin and
1.1 Gm. per cent gamma globulin. Pulmonary
hypertension with exercise was demonstrated on
right heart catheterization.
In January, 1966, she began to have headaches
and was found to be hypertensive. At this time
there was an increase in generalized weakness and
MEDSGER, RODNAN, MOOSSY, WTER
fatigability, as well as anorexia and dysphagia.
Three weeks after beginning to take prednisone
(20 mg./day), the patient, suddenly became restless, obtunded, and comatose. She was transferred
to Presbyterian-University Hospital. She had lost
22 per cent of her previous weight. On admission
the blood pressure was 210/120, and the pulse
100/min. The respiration was Cheyne-Stokes in
character. There was nuchal rigidity, blurring of
the left optic disc, decreased deep tendon reflexes
in the left arm and leg, and bilateral Babinski
signs. The hemoglobin was 14.2 Gm. per cent,
hematocrit 45 per cent, and white cell count
14,000/cu.mm. with 93 per cent neutrophilic
leukocytes. Lumbar puncture yielded xanthochromic cerebrospinal fluid containing many red
blood cells, confirming the clinical impression of
subarachnoid hemorrhage. The blood urea nitrogen was 25 mg. per cent and serum creatinine 1.5
mg. per cent. Arteriograms and brain scan were
normal. There was a gradual increase in responsiveness, and the localizing neurologic signs disappeared. Blood pressure was controlled with
alpha methyldopa.
After the patient had improved considerably,
muscle evaluation was performed. She complained
of no aching or tenderness. There was profound
weakness of shoulder and pelvic girdles, and she
was unable to perform work against any resistance
with these muscle groups. Quadriceps atrophy
was present, but anterior tibial and posterior tibial
functions were fair. Forearm muscles were fair
but interossei and thenar muscles were weak.
weakness.
The overall rating was
Serum transaminase (SGOT), LDH, and CPK
values were normal. The serum aldolase activity
was 6.13 milliunits/ml. Urine creatinine was 0.43
Gm./24 hours, urine creutine 355 mg., and the
creatinine coefficient 75 per cent of that predicted
for her new weight (at this time the patient had
been off corticosteroids for 4 weeks). The blood
urea nitrogen was 20 mg. per cent. During the
sixth hospital week, she became oliguric and
lapsed into congestive heart failure. She did not
respond to digitalis and diuretics, developed refractory pulmonary edema, and expired.
At post-mortem examination, the chief finding
was that of renal vascular lesions indistinguishable from those seen in malignant hypertension.
There was pulmonary and myocardial fibrosis and
extensive disease of the esophagus characteristic
of PSS. The diaphragm, deltoid, and quadriceps
muscles all showed pathologic changes. Frank
muscle necrosis and eosinophilic floccular changes
++++
567
SKELETAL MUSCLE INVOLVEMENT IN PSS
were present (Fig. 2). In the interstitium, fat and
connective tissue were increased, with extensive
fibrosis and some areas of calcification. Chronic
inflammatory cells were scattered throughout,
and there were small perivascular cellular collections (Fig. 3).
SUMMARIO
IN INTERLINGUA
Cinquanta-tres patientes con typic sclerosis systemic progressive (SSP) esseva examinate pro evidentia de myoasthenia, anormal enzymas seral, disturbation del creatina e
creatinina urinari, e alterationes histopathologic in tissu de musculo skeletic. In le majoritate del casos, characteristicas clinic e biochimic de myopathia primari esseva notate.
Affection microscopic de fibras o de interstito muscular esseva presente in 14 de 36
casos. Le anormalitate le plus uniformemente presente esseva fibrosis interstitial. Le
affection muscular es reguardate como un importante characteristica del curso clinic
de SSP.
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