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Intravenous pulse methylprednisolone treatment of juvenile dermatomyositis.

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328
BRIEF REPORT
INTRAVENOUS PULSE METHYLPREDNISOLONE TREATMENT
OF JUVENILE DERMATOMYOSITIS
RONALD M. LAXER, LEONARD D. STEIN, and ROSS E. PETTY
Recent observations that juvenile dermatomyositis (JDMS) may be a heterogenous disorder, in both its
clinical course and prognosis, suggest that subgroups of
patients with this disease may respond to various modes
of therapy. Therefore, current treatment recommendations of daily, long-term oral corticosteroid treatment,
with its attendant side effects, may not be necessary for
all children with JDMS. We report the results of treatment with high-dose, pulse intravenous methylprednisolone in 7 children with JDMS, 3 of whom had an
excellent response with complete remission and no need
for daily steroid therapy. We suggest that patients with
early, mild JDMS may be candidates for therapy with
intravenous methylprednisolone.
Juvenile dermatomyositis (JDMS) is an inflammatory, multisystem disorder of unknown etiology,
with predominant involvement of muscle and skin (1).
The diagnosis of JDMS rests on the presence of
Presented in part at the Annual Meeting of the American
Academy of Pediatrics, New York, NY, October 1982.
From the Division of Immunology/Rheumatology, The
Hospital for Sick Children, University of Toronto, Toronto,
Ontario, Canada; the Division of Pediatric Rheumatology, British
Columbia’s Children’s Hospital; and the University of British Columbia, Vancouver, British Columbia, Canada.
Ronald M. Laxer, MDCM, FRCP(C): Assistant Professor
of Pediatrics, University of Toronto, and Assistant, Canadian Arthritis Society; Leonard D. Stein, MD: Assistant Professor of
Pediatrics, University of Toronto, and Assistant, Canadian Arthritis
Society; Ross E. Petty, MD, PhD, FAAP: Head, Division of
Pediatric Rheumatology, British Columbia’s Children’s Hospital,
and Professor of Pediatrics, University of British Columbia.
Address reprint requests to Ronald M. Laxer, MDCM,
FRCP(C), Division of Immunology/Rheumatology, The Hospital for
Sick Children, 555 University Avenue, Toronto, Ontario, Canada
M5G 1x8.
Submitted for publication January 29, 1986; accepted in
revised form August 8, 1986.
Arthritis and Rheumatism, Vol. 30, No. 3 (March 1987)
characteristic proximal muscle weakness, skin rash,
and elevated serum levels of 1 or more muscle enzymes. Muscle biopsy and electromyography (EMG)
may provide confirmatory information.
Early treatment with high doses of corticosteroids, followed by long-term, low-dose maintenance
therapy adjusted in accordance with clinical and enzyme changes, has become the mainstay of treatment
of JDMS, and is believed to be the therapeutic basis of
the relatively good prognosis in this disorder (2).
However, this regimen is associated with the wellknown side effects of long-term steroid therapy. These
range from cushingoid features and osteoporosis to
growth retardation, cataracts, and hypertension.
In an attempt to minimize toxicity while maintaining therapeutic effects, variations in corticosteroid
administration schedules have been used. One such
approach is the use of high-dose intravenous methylprednisolone, which has been reported to be effective
in the treatment of lupus nephritis (3) and a number of
other rheumatic disorders, including polymyositis and
dermatomyositis (4-6). Because of apparent benefit,
lack of significant side effects, and the known side
effects of high-dose daily steroid use, we elected to use
intravenous pulse methylprednisolone (IVMP) as the
initial treatment in a child with JDMS. His excellent
response prompted trials with this form of therapy in
an additional 6 children. That experience is the subject
of this report.
CASE REPORTS
Diagnosis and treatment. Seven patients with
JDMS who had been seen consecutively over a period
of 3 years were treated with IVMP. Patients 1-6 were
BRIEF REPORTS
329
Table 1. Characteristics of 7 patients with juvenile dermatomyositis at presentation to the rheumatology clinic*
Symptom duration
(months)
Muscle enzymes
Patient
Ageisex
Skin
Muscle
CK
LDH
SGOT
EMG
Biopsy
ANAt
RF
1
2
3
4
5
6
7
9lM
11IF
6/F
13/F
4iM
5/F
16iM
1.5
27
1.5
6
14
14
6
1
2
64 I
320
3,730
598
335
1,543
402
52
ND
ND
Abn
Abn
Abn
ND
Abn
ND
ND
Abn
ND
Abn
ND
Abn
-
-
2+ fine speckled
2+ homogeneous
I + fine speckled
I : 1,280 speckled
-
15
16
24
<1
2
199
I54
3,240
1,725
556
987
ND
47
83
54
44
I57
80
-
-
* CK = creatine kinase. normal <I50 unitsiliter; LDH = lactate dehydrogenase, normal 1210 unitsiliter; SGOT = serum glutamic oxaloacetic
transaminase, normal <35 unitsiliter; EMG = electromyography; ANA = antinuclear antibody; RF = rheumatoid factor (by latex
agglutination); ND = not done; - = negative; Abn = abnormal findings.
t Performed on HEp-2 cells; results from patients 1-6 read as intensity of fluorescence at 1530 titer, patient 7 end-titered. All sera negative
against Sm, ribonucleoprotein, native DNA, Ro, and La. Not tested against PM-I.
seen at the Rheumatology Clinic, British Columbia’s
Children’s Hospital (Vancouver, British Columbia,
Canada); patient 7 was seen at the Rheumatology
Clinic, The Hospital for Sick Children (Toronto,
Ontario, Canada). The diagnosis of JDMS in these
patients was based on the triad of characteristic skin
findings, proximal muscle weakness, and elevated
serum levels of muscle enzymes (Table 1). EMGs were
performed on 4 patients, and muscle biopsy specimens
were taken from 3 patients. These procedures had
been undertaken prior to referral of these individual
patients to the Rheumatology Clinic. In cases where
the combination of the clinical history, rash, and
proximal myopathy were thought to be unquestionably
those of JDMS, however, it was felt that these investigations would not aid the diagnosis, and they were
therefore not performed. The duration of symptoms
prior to treatment ranged from 1 month to 27 months,
and 2 children had received oral corticosteroids prior
to treatment with IVMP.
The medication used in all cases was methylprednisolone sodium succinate. It was administered
intravenously (30 mg/kg/dose; maximum 1 gm in patient 7), diluted in a total volume of 100 cc of 5%
dextrose in water, and infused over 2-3 hours with
frequent monitoring of the vital signs. The initial
treatment course was given daily for 3 consecutive
days (except for patient 6, who received treatment for
1 day only) while the patient was in the hospital. Subsequent treatment, based on the patients’ clinical and
biochemical status, usually involved only 1 pulse per
course, and was administered on an outpatient basis,
with constant monitoring by 1 of the investigators.
Because not all patients were investigated with
muscle biopsy or EMG, we felt it was inappropriate to
apply the criteria of Bohan and Peter (7) for the
diagnosis of JDMS to these patients; however, all 4
who underwent an EMG and/or a muscle biopsy
satisfied criteria for definite JDMS, while the other 3
had probable JDMS according to these criteria.
The initial course of IVMP caused a rapid fall in
the serum level of muscle enzymes in all patients, but
the long-term effects varied considerably, as illustrated by the following case reports (Tables 1 and 2).
Patient 1. The patient, a 9-year-old boy, presented with a 6-week history of malaise; lethargy; rash
on his face, proximal interphalangeal (PIP), and
metacarpophalangeal (MCP) joints, elbows, and
knees; and progressive proximal muscle weakness.
Examination showed a scaly, erythematous dermatitis
over the MCP and PIP joints, elbows, and knees, and
facial erythema. There was mild, but definite, symmetric muscle weakness that affected the neck flexors,
shoulder, and hip girdle musculature, tightness of the
hamstring muscles, and marked tenderness of the
shoulder girdle musculature. The serum levels of muscle enzymes were elevated. Treatment was initiated
with IVMP, and the muscle enzyme levels fell rapidly
to normal and have remained so. The muscle weakness resolved over 4-5 months, and the hamstring
tightness resolved after 18 months. The skin rash
disappeared over 6 months, and he is completely free
of disease at 5 years of followup.
Patient 2. Patient 2, an 11-year-old girl, had a
2-year history of photosensitivity, heliotrope rash,
Gottron’s papules over the MCP and PIP joints, and
dilated periungual capillaries. Although she remained
fully active, she had noticed muscle weakness during
BRIEF REPORTS
330
Table 2. Course of 7 patients with juvenile dermatomyositis following treatment with intravenous pulse methylprednisolone (IVMP)
Patient
History
of
weakness
(months)
Category*
1
2
1.5
6
P
P
3
14
D
4
14
D
5
6
D
6
7
1
2
P
D
IVMP
frequency
Daily x 3 days
Daily x 3 days; weekly
x 2 weeks.
Daily X3 days; weekly
x 4 weeks; twice
weekly x 4 wzeks.
Daily x 3 days; weekly
x 5 weeks.
Daily x 3 days; rwice
weekly x 4 weeks.
1 day
Daily x 3 days; weekly
x 4 weeks.
Oral steroid
treatment
Postdiagnosis
followup
(years)
Outcome
Skin?
Muscle
strength
Calcinosis
None
None
5
5
Normal
Mild GP
Normal
Normal
None
None
Dose tapered over
2 years
4
Normal
Normal
Transient
Dose tapered over
2 years
Dose tapered over
2 years
None
Dose tapered over
18 months
4
PVR
Transient
4
PVR
Persistent
weakness
Normal
1.5
2
Mild GP
Normal
Normal
Normal
Multiple,
persistent
None
None
* P = probable, D = definite, as suggested by Bohaq and Peter (ref. 7 ) .
t GP = Gottron's papules; PVR = persistent vasculitic rash
the previous 6 months. Serum levels of muscle enzymes were only slightly elevated. She was treated
with an initial 3-day course of IVMP, and required 2
further, single IVMP pulses 3 and 4 weeks after the
initial treatment, to normalize her muscle enzyme
levels. Two months after therapy was started, her
strength returned to normal. The cutaneous manifestations of her disease have slowly diminished during
the 5 years of followup, and she has not required any
further treatment.
Patient 3. The patient, a 6-year-old girl, had a
rash for 5 months and muscle weakness for 3 4
months. She had facial erythema, a heliotrope rash,
Gottron's papules over the MCP and PIP joints, scaly
erythema over her elbows and knees, and dilated
periungual capillaries. There was marked proximal
muscle weakness. EMG results showed polyphasic
units with fibrillations at rest and increased insertional
activity, and muscle biopsy findings showed a
lymphocytic infiltrate, atrophic muscle fibers, and mild
fibrosis. Serum levels of all muscle enzymes were
elevated. She was treated initially with prednisone (2
mglkglday, in divided doses) and had a good clinical
and biochemical response. Because of the development of severe cushingoid features, however, the
prednisone was discontinued, and she became increasingly weak. She was referred to our clinic 10 months
after the initial diagnosis, at which time all muscle
enzyme levels were markedly abnormal. Treatment
with IVMP resulted in a marked, but transient, decline
in the creatine kinase (CK) level (Figure 1). She was
eventually treated with IVMP (15 mglkglpulse, twice
weekly), and although her strength was improving, the
need for such frequent pulses led to treatment with
oral prednisone (1 mg/kg/day). She responded well
with marked improvement in her muscle strength and
normalization of her muscle enzyme values 3 months
later. Muscle strength slowly returned to normal while
the steroids were being tapered over 2 years. She
developed 1 transient calcific deposit in her left
popliteal fossa. She has not received corticosteroids
for 2 years and is clinically normal.
Patient 4. The patient, a 13-year-old Chinese
girl, had initially received 2 courses of daily oral
prednisone for what was diagnosed elsewhere as systemic lupus erythematosus. She was referred to us
because of severe muscle weakness and dysphagia.
She had a heliotrope rash, scaly erythematous
dermatitis over the PIP and MCP joints, elbows, and
knees, and had dilated nailfold capillaries. The serum
levels of muscle enzymes were elevated and the antinuclear antibody (ANA) was negative. EMG findings
showed spontaneous fibrillations, polyphasic potentials, and decreased amplitude. An initial 3-day course
of IVMP was followed by treatment once a week for 5
weeks. The serum levels of muscle enzymes declined
to normal, and over the next several weeks, untreated,
her muscle strength slowly improved. Subsequently,
she worsened dramatically over 1 week, and became
bedridden 4 months into her disease course. One pulse
treatment did not improve her weakness. She was then
treated with prednisone (1 mglkglday, in divided
doses), with very gradual, partial resolution of her
weakness and rash over 4 years. She had 1 episode of
BRIEF REPORTS
4000
33 1
1
1u1
I
I
10
1
20
ll
I
30
1 1 4
I
40
C C C C
I
I
I
1
t
50
60
70
80
90
DAYS
Figure 1. Response of patient 3 to intravenous methylprednisolone, as demonstrated in the serum levels of
creatine kinase. Long arrows indicate dosage of 30 rng/kg; short arrows indicate dosage of 15 mg/kg.
a localized calcium deposit which has completely
resolved. She no longer requires corticosteroid therapy, and her cutaneous disease and muscle strength
continue to improve.
Patient 5. Patient 5 , a 4-year-old Filipino boy,
had a skin rash that was treated with topical steroids
for 2 years, and a 6-month history of muscle weakness.
On examination, there was periorbital edema with a
heliotrope discoloration of the eyelids, marked cutaneous atrophy, Gottron’s papules over the PIP and
MCP joints, scaly erythema over the elbows and
knees, and dilated nailfold capillaries. Proximal muscle weakness was evident. EMG findings were indicative of an inflammatory myopathy, and muscle biopsy
results showed an interstitial lymphocytic infiltrate,
type I1 fiber atrophy, and minimal capillary thrombosis. Serum levels of muscle enzymes were elevated.
He required twice-weekly treatments with IVMP to
maintain his muscle enzyme levels within the normal
range, and his muscle strength slowly improved. Be-
cause of the need for frequent IVMP therapy, oral
prednisone (0.5 mglkglday , in divided doses) was
substituted, with good response. His muscle strength
and muscle enzyme levels slowly returned to normal
while prednisone was being reduced over 2 years. He
has had several areas of subcutaneous calcification
and his skin changes persist 5% years after onset.
Prednisone has been discontinued, and his muscle
strength is normal.
Patient 6. The patient, a 5-year-old girl, presented with a 1-month history of weakness and tenderness in the muscles of her thighs. This resulted in an
inability to walk independently, and she had difficulty
rising from a lying or sitting position. Two weeks after
onset of the muscle weakness, she developed prominent livedo reticularis of the skin of the limbs,
erythema over the PIP joints, and patchy dryness at
the lateral canthi of her eyes. There was capillary
dilatation in the periungual region of both fourth
fingers. Serum levels of muscle enzymes were all
BRIEF REPORTS
332
4000L
3500
3000
-
2500
-
2000
-
1500
-
1000
-
10
23
30
40
50
120
DAYS
Figure 2. Serum levels of creatine kinase of patient 6. Arrow indicates administration of 1 bolus of intravenous
methylprednisolone (30 mg/kg).
markedly elevated. She was given one IVMP pulse,
and there was a prompt decline in all muscle enzyme
levels to normal within 8 days (Figure 2). Her symptoms have entirely disappeared, and muscle strength is
normal at followup 18 months later, although mild
livedo reticularis and Gottron’s rash persist. She has
required no other therapy.
Patient 7. The patient, a 16-year-old boy, complained of arthralgias of the elbows, wrists, knees, and
ankles. He also had mild Raynaud’s phenomenon, and
some tightness of the skin over his hands and face. He
was treated with naproxen, but returned several
months later and complained of a rash over the PIP
joints and of muscle weakness. Examination revealed
mild, but definite, symmetric proximal muscle weakness, a heliotrope discoloration of the eyelids, Gottron’s papules over the PIP joints, linear nailfold hemorrhages and infarcts, and hepatosplenomegaly . There
was some tightness of the skin over his hands. Serum
levels of muscle enzymes were elevated. EMG find-
ings showed increased insertional activity and polyphasia. Muscle biopsy results of the deltoid showed ?
widespread perivascular cuffing, mild vasculitis,
perifascicular atrophy, and focal segmental fiber degeneration and regeneration. H e was thought to have
an overlap syndrome with features of scleroderma, but
predominantly of dermatomyositis. H e was treated
with IVMP (1 gm daily for 3 consecutive days, followed by weekly IVMP). His weakness and arthralgias
improved, and the serum levels of muscle enzymes
diminished markedly, but transiently, following
IVMP. The weekly IVMP was discontinued after 1
month and prednisone (1 mg/kg, 60 mg/day, in divided
doses) was begun. H e has done well, and at 2 years
followup is no longer receiving prednisone. His
strength and serum levels of muscle enzymes are
normal, and his rash has disappeared.
Side effects. A number of side effects directly
attributable to intravenous methylprednisolone were
observed during the course of therapy. Three of 7
BRIEF REPORTS
patients, in a total of 5 of 50 pulses, developed mild
transient hypertension. In all cases, this responded
promptly to a slowing of the infusion rate. Patient 5 ,
who was treated twice weekly for 4 weeks, developed
mild cushingoid facies. Patient 7 complained on 2
occasions of a “belligerent” feeling and felt the need
to be moving. All patients complained of a metallic
taste during the infusion.
DISCUSSION
The treatment recommendations for JDMS
have evolved over the last 30 years as more clinical
experience has accumulated. Current recommendations comprise initial treatment with prednisone, 2
mg/kg/day administered in 3 4 divided doses (1). This
is usually continued for at least 4-6 weeks, or until
there is clinical and biochemical evidence of improvement. The dose is then slowly consolidated and reduced over a period of 1-2 years. Both Spencer et al
(8) and Bowyer et a1 (9) have recently reported that the
course of JDMS may not be homogeneous, and they
have identified several courses of JDMS. Both have
suggested that patients with different disease courses
may respond to different forms of treatment. Patients
1 , 2, and 6, who did not require daily corticosteroid
treatment, probably fit into the “monocyclic” course
defined by Spencer et a1 (8) or the “monophasic”
course described by Bowyer et a1 (9). It is important to
determine, at the time of diagnosis, which course
patients will follow. Therapy might then be individually tailored, with a resultant decrease in steroid
toxicity. Crowe et a1 (10) reported that the result
of muscle biopsy at diagnosis might be a useful prognostic indicator, but this has not been confirmed by
others (1 1).
Cathcart et a1 (3) reported the beneficial effects
of IVMP in the treatment of lupus nephritis in 1976,
and since that time, IVMP has been used with good
results in a large variety of rheumatic disorders, including rheumatoid arthritis (12), polymyositis (4), and
in children with juvenile rheumatoid arthritis, ankylosing spondylitis, sarcoidosis, and Behqet’s disease (6).
Reports of the use of pulse steroids in JDMS are
sparse. Miller (6) described a 13-year-old girl with a
3-month history of JDMS who did not improve with
high-dose prednisone and methotrexate. Treatment
with pulse hydrocortisone resulted in dramatic improvement and facilitated tapering of the daily dose of
corticosteroid. Fessel (4) reported the case of a 22year-old woman whose disease flared several years
333
after a remission that had been induced by high-dose
prednisone. Although her CK level diminished significantly soon after pulse methylprednisolone administration, it quickly rebounded and was associated with
increasing weakness that required maintenance
prednisone therapy. Silverman et a1 (13) studied 1
patient with JDMS whose only management consisted
of single pulses of methylprednisolone.
Dramatic changes in serum levels of CK were
observed in our patients in response to IVMP. This
effect was noted within 24 hours following drug administration; however, in several of our patients this effect
was short-lived, and CK levels rebounded to pretreatment values within days. This experience is similar to
that previously reported (5). The kinetics of the CK
response to oral steroids have not been documented
carefully in JDMS, although a gradual fall in serum
muscle enzyme levels is seen with high-dose daily
administration. Elevated levels of CK in Duchenne’s
muscular dystrophy, a noninflammatory degenerative
myopathy , may diminish significantly in response to
high-dose daily oral steroids (14). Wagner and Critz
(15) have shown that high doses of prednisone, given
to dogs just prior to exercise, can decrease the expected rise in CK by as much as 50%. These observations may imply that the acute, but short-lived, reductions in CK seen in some of our patients may not
reflect the immunosuppressive or antiinflammatory
effects of corticosteroids, but perhaps represent an
effect of steroids on muscle membrane stabilization or
on renal clearance of CK.
JDMS represents a spectrum of severity of
disease, and patients with minimal disease, as determined by degree of muscle weakness, level of muscle
enzymes, or duration of disease, may respond to a
brief, but intense, steroid effect. Although the 3 patients who required only IVMP as treatment met
Bohan and Peter’s criteria for probable JDMS (7), we
believe that this is because these patients had undergone neither muscle biopsies nor EMG. We could not
predict by age, sex, duration of weakness prior to
pulse therapy, level of muscle enzymes, ANA status,
or response to the initial course of IVMP, which
patients would require further treatment with oral
steroids. Two of the 4 patients in whom it was necessary to administer daily doses of prednisone (patients
3 and 4) had received previous short courses of oral
corticosteroid therapy. Inadequate initial treatment
has been shown to lead to a greater number of functional limitations and a greater amount of calcinosis in
patients with JDMS (9); thus, it is not surprising that
334
BRIEF REPORTS
these 2 children did not respond to treatment with
IVMP alone.
Side effects of intravenous methylprednisolone
were infrequent and mild in the patients described
herein. Although multiple side effects have been reported in adults with various disorders treated with
pulse corticosteroids (16), we are unaware of similar
manifestations in children. This is in contrast with the
universal occurrence of significant cushingoid side
effects and growth retardation, as well as the other
side effects, which result from daily oral corticosteroid
therapy.
We believe that IVMP may have a therapeutic
role in early, mild JDMS. It is easy to administer and
probably has less overall toxicity than high-dose daily
prednisone. The disease identified clinically as JDMS
has great heterogeneity, ranging from the relatively
mild disease we saw in patients 1, 2, and 6 , through
disease of significant chronicity and morbidity. While
it is undeniable that survival and long-term muscle
function are attributable to the intensive use of
corticosteroids, it is also probable that certain patients
would respond well to much briefer courses of
corticosteroids and not have significant side effects.
Recognition of the heterogeneity of the disease, and
the dramatic and apparently long-lasting effects of
intravenous methylprednisolone in a portion of these
children with the diagnosis of JDMS, makes individualization of therapy possible.
Acknowledgments. The authors thank Dr. P. Melton
for obtaining followup laboratory data for patient 6, E. Laxer
for editorial assistance, and Laurie Llew-Williams for secretarial assistance.
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