Childhood
Dermatomyositis
and
Polymyositis
Treatment With Methotrexate and Prednisone Thomas J. Fischer, MD; Gary S.
Rachelefsky, MD; Robert B. Klein, MD;
\s=b\ The conditions of three children with
dermatomyositis and one child with polymyositis were treated for nine to 31 months with combined prednisone and intravenous methotrexate (1 mg/kg/wk) when prednisone alone was ineffective in controlling the disease or when there were substantial steroid-related toxic effects. All children showed a major clinical improvement within three months despite concomitant reduction of the prednisone dose. Three children completely recovered; one patient relapsed and died. The toxic effects of methotrexate included elevated liver transaminases (3/4), nausea (2/4), abdominal pain (2/4), bone pain (2/4), mild neutropenia (1/4), and mild pruritus (1/4). Intravenous methotrexate is an effective adjunct to steroid therapy in the treatment of steroid-resistor life-threatening dermatomyositis\x=req-\ polymyositis or dermatomyositis-polymyositis complicated by severe steroid\x=req-\
ant
related effects. (Am J Dis Child 133:386-389,
1979)
Corti costeroidmorbidity ity dermatomyositis.1"1 treatment has
re¬
duced the and mortal¬ of childhood Despite corticosteroid therapy, a small number of these children continue to have progressive disability4 and sub¬ stantial steroid-related complications like hypertensive encephalopathy or cataracts. Some publications'" sug¬ gest that immunosuppressive agents are a beneficial adjunct to conventionFrom the Departments of Pediatrics (Drs Fischer, Rachelefsky, Klein, and Stiehm) and Medicine (Dr Paulus), UCLA School of Medicine,
Angeles. Dr Fischer is now with the University of Cincinnati, Children's Hospital Medical Los
Center. Dr Klein is now with the Dartmouth Hitchcock Medical Center, Hanover, NH.
Reprint requests to Department of Pediatrics, UCLA School of Medicine, 10925 LeConte Ave,
Los
Angeles,
CA 90024 (Dr
Stiehm).
al steroid
Harold E. Paulus, MD; E. Richard Stiehm, MD
therapy in severely affected
children. This study reports the results of combined therapy with prednisone and intermittent doses of intravenous (IV) methotrexate in four children. SUBJECTS AND METHODS The
based
diagnosis on
the
of dermatomyositis was following five criteria:
symmetrical proximal muscle weakness; elevated muscle enzymes (creatinine phosphokinase [CPK] and/or aldolase); charac¬ teristic electromyographic changes, includ¬ ing fibrillation potentials, insertional irritability, positive sharp waves, lowamplitude polyphasic potentials, and pseudomyotonic discharges; typical histologie changes on muscle biopsy specimen (mus¬ cle fiber atrophy, degeneration, necrosis, mononuclear cell infiltration, and fibrosis); and characteristic skin involvement, in¬ cluding heliotropic discoloration of the eyelids and an erythematous, scaly erup¬
tion over the extensor surfaces of the extremities. Except for the patient with polymyositis (case 2) who lacked the typical rash, all patients satisfied these criteria. Two patients (cases 1 and 4) had evidence of vasculitis in addition to the aforemen¬ tioned muscle biopsy findings. Initial therapy consisted of prednisone (1.2 to 2.9 mg/kg/day). Intravenous metho¬
trexate (approximately 1 mg/kg/wk) was added if one of the following criteria was present: (1) lack of clinical response after three months of daily corticosteroid thera¬ py, (2) rapid progression of disease leading to respiratory failure and/or substantial dysphagia, or (3) intolerable steroidinduced side effects (Table 1). With evidence of sustained improvement in muscle strength and a decrease in muscle enzymes, methotrexate therapy was grad¬ ually decreased to biweekly, triweekly, and finally, monthly doses. Patients had com-
Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/11/2015
píete blood
cell (CBC) counts done before each methotrexate injection and were observed especially for stomatitis, sore throat, purpura, fever, and gastrointestinal (GI) complaints. Measured weekly or biweekly were CPK levels (normal, 33 to 78 units/L [females] and 32 to 112 units/L [males]), SGOT levels (normal, 6 to 36 IU/L), and SGPT levels (normal, 10 to 45 IU/L). Normal serum aldolase values are 3 to 8 units/L. Urine and level of BUN were monitored periodically. Clinical improve¬ ment was also reported with serial muscle testing (using the grading system of the Medical Research Council)'- and electromyograms. All four patients were treated at UCLA; informed consent was obtained in accordance with the regulations of the UCLA Human Subjects Protection Com¬ mittee. Clinical data, response to therapy, and methotrexate dosage and toxicity are given in Tables 1, 2, and 3, respectively.
REPORT OF CASES Case 1.—An 11-year-old boy was admit¬ ted to UCLA Hospital with a seven-month history of an erythematous rash and diffuse muscle weakness and tenderness, primarily of the neck and proximal muscles of his extremities. Findings of muscle elevations, electromyogram enzyme (EMG), and muscle biopsy specimen were abnormal. An antinuclear antibody (ANA) was negative. Prednisone therapy (60 mg/ day) was started. Despite an episode of mumps encephalitis, his condition gradual¬
ly improved over eight months, requiring 40 mg of prednisone per day. At this time, bilateral-posterior subcapsular cataracts were observed. Ophthalmologic consulta¬
tion confirmed the presence of these steroid-induced cataracts and recom¬ mended immediate reduction in predni¬ sone dosage to avoid severe vision loss. Methotrexate therapy (25 mg/wk) was started in an attempt to facilitate a decrease in prednisone dosage. Over a peri-
Table 1.—Clinical Characteristics of Patients Who Received Methotrexate Initial Disease Manifestations
Creatinine/
Weight Case/ Sex
Before Methotrexate
Current
Therapy, kg
yr 16
1/M
Age
Onset,
Age,
33.4
of
yr
Proximal Muscle Weakness
Muscle
Treatment Before Methotrexate
Biopsy
Therapy
Phosphokinase
and/or Aldolase
Levels, Units/L
Rash
EMG
44/11
11
Prednisone, 40
mg/day 2/F
128/14
14.9
Prednisone, 10 mg four times per day
Indications for Methotrexate Use
Steroid-induced pos¬ terior cataracts Continued muscle weakness; marked cushingoid fea¬ tures; osteoporosis
(spine) oral and vaginal moniliasis
47.5
3/F
12
16
1,136/73
Prednisone, 15 mg four times per day
4/M
26.4
9
6,300/*
Prednisone, 15
(Patient died)
mg four times per day
Continued muscle
weakness; hyper¬ tensive
enceph¬ alopathy
Continued muscle weakness with dys¬
phagia and respira¬ tory impairment
"Not determined.
Table Duration of Methotrexate
Therapy,
2—Steroid-sparing Effect
of Methotrexate
Therapy
Proximal Muscle
Dosage
mo
Creatinine
Phosphokinase
Strength,
Prednisone
0-to-5 Scale"
EMG
and/or Aldolase Levels, Units /L
Case 1 0
40 mg
3
60 mg every other 25 mg every other 20 mg every other 20 mg every other
6 9 12
daily day day day day
4/5 5/5 5/5 5/5 5/5
14/NDt
Normal Normal Normal Normal
48/ND 30/ND
Normal
50/ND
16/11
Case 2 0 3 6 9 12
10 mg 4
times/day
30 mg every other
day 15 mg every other day 15 mg every other day 15 mg every other day
3-4/5
Abnormal
12/ND
4/5 4+/5
Improved
96/22
ND
52/14
4+/5 4+/5
Normal ND
44/9
2-3/5
Abnormal
3/5
Improved Improved
44/ND
Case 3 15 mg 4 times/day 20 mg every other day 20 mg every other day 20 mg every other day 12
3-4/5
344/7 86/ND
4/5
No
118/ND 84/ND
20 mg every other day
4/5
change Improved
148/ND
15 mg 4
Case 4
12
60 mg
times/day daily
2-3/5 3/5
25 mg 35 mg
daily daily
3/5 2/5
No
change Improved ND
2760/20 151/11 56/4
326/ND
Patient died
"Medical Research Council Grading not determined.
tND indicates
Abnormal
System.
od of 11 months he received 32 doses of methotrexate (total dose, 800 mg) with
progressive muscle-strength improvement and a decrease in steroid dose (20 mg every other day) and size of the cataracts. Methotrexate-related toxic effects included occa¬ sional transient nausea postinjection and one episode of transient elevation of SGPT
clumsiness. She could not stand or sit with¬ out support. Findings of muscle enzyme elevations, EMG, and muscle biopsy speci¬ men were characteristic of polymyositis. An ANA was negative. Prednisone, 20 mg twice daily for one month, produced
improvement. Alternate-day prednisone therapy (60 mg) for two months was asso¬
ciated with substantial deterioration of muscle strength. Despite the resumption of daily prednisone (10 mg four times a day) for four months, there was no improve¬ ment in muscle strength and substantial cushingoid features, oral and vaginal moniliasis, weight gain, and osteoporosis of the spine also developed. Intravenous metho¬ trexate therapy, 20 mg/wk, was begun. She received 39 doses over ten months (total dose, 780 mg). After three months of ther¬ apy, muscle strength and EMG substantial¬ ly improved, while prednisone dosage decreased to 30 mg every other day. Over the next nine months, while she was receiv¬ ing 15 mg of prednisone every other day, her condition remained stable. Her cushin¬ goid features improved and her weight decreased (27.5 to 23.2 kg). Except for occasional mild abdominal pain immediate¬ ly after methotrexate administration, she had no toxic reaction. At age 8 years, three years after her last dose of methotrexate, she is well while receiving prednisone (2
mg/day).
level. At 16 years of age, three years after methotrexate therapy was stopped, he has minimal muscle weakness controlled with low-dosage prednisone (10 mg every other
day).
Case 2.-A
4-year-old girl was admitted Hospital with a six-month history muscle weakness, waddling gait, and
to UCLA
of
Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/11/2015
Case 3.—A 12-year-old girl was admitted to UCLA Hospital with a four-week history
of progressive muscle weakness and heliotropic rash. Findings of physical examina¬ tion, muscle enzyme elevations (CPK, 12,960 units/mL), EMG, and muscle biopsy specimen were characteristic of dermatomyositis. An ANA was negative. Predni¬ sone (10 mg four times a day) produced
Table 3.—Methotrexate Treatment Data in Cases of
Duration, Case
Cumulative Dose, mg 800
Doses 32
Mg/kg/Dose
11
14
39
0.7-0.9
780
31
107
0.7-0.9
4,580
mo
1.3
Dermatomyositis
and
Clinical Response Steroid dose reduced; cataract size reduced; muscle strength normal¬ ized Steroid dose reduced; weight reduc¬ tion (
Dermatomyositis
and
Polymyositis
Treatment With Methotrexate and Prednisone Thomas J. Fischer, MD; Gary S.
Rachelefsky, MD; Robert B. Klein, MD;
\s=b\ The conditions of three children with
dermatomyositis and one child with polymyositis were treated for nine to 31 months with combined prednisone and intravenous methotrexate (1 mg/kg/wk) when prednisone alone was ineffective in controlling the disease or when there were substantial steroid-related toxic effects. All children showed a major clinical improvement within three months despite concomitant reduction of the prednisone dose. Three children completely recovered; one patient relapsed and died. The toxic effects of methotrexate included elevated liver transaminases (3/4), nausea (2/4), abdominal pain (2/4), bone pain (2/4), mild neutropenia (1/4), and mild pruritus (1/4). Intravenous methotrexate is an effective adjunct to steroid therapy in the treatment of steroid-resistor life-threatening dermatomyositis\x=req-\ polymyositis or dermatomyositis-polymyositis complicated by severe steroid\x=req-\
ant
related effects. (Am J Dis Child 133:386-389,
1979)
Corti costeroidmorbidity ity dermatomyositis.1"1 treatment has
re¬
duced the and mortal¬ of childhood Despite corticosteroid therapy, a small number of these children continue to have progressive disability4 and sub¬ stantial steroid-related complications like hypertensive encephalopathy or cataracts. Some publications'" sug¬ gest that immunosuppressive agents are a beneficial adjunct to conventionFrom the Departments of Pediatrics (Drs Fischer, Rachelefsky, Klein, and Stiehm) and Medicine (Dr Paulus), UCLA School of Medicine,
Angeles. Dr Fischer is now with the University of Cincinnati, Children's Hospital Medical Los
Center. Dr Klein is now with the Dartmouth Hitchcock Medical Center, Hanover, NH.
Reprint requests to Department of Pediatrics, UCLA School of Medicine, 10925 LeConte Ave,
Los
Angeles,
CA 90024 (Dr
Stiehm).
al steroid
Harold E. Paulus, MD; E. Richard Stiehm, MD
therapy in severely affected
children. This study reports the results of combined therapy with prednisone and intermittent doses of intravenous (IV) methotrexate in four children. SUBJECTS AND METHODS The
based
diagnosis on
the
of dermatomyositis was following five criteria:
symmetrical proximal muscle weakness; elevated muscle enzymes (creatinine phosphokinase [CPK] and/or aldolase); charac¬ teristic electromyographic changes, includ¬ ing fibrillation potentials, insertional irritability, positive sharp waves, lowamplitude polyphasic potentials, and pseudomyotonic discharges; typical histologie changes on muscle biopsy specimen (mus¬ cle fiber atrophy, degeneration, necrosis, mononuclear cell infiltration, and fibrosis); and characteristic skin involvement, in¬ cluding heliotropic discoloration of the eyelids and an erythematous, scaly erup¬
tion over the extensor surfaces of the extremities. Except for the patient with polymyositis (case 2) who lacked the typical rash, all patients satisfied these criteria. Two patients (cases 1 and 4) had evidence of vasculitis in addition to the aforemen¬ tioned muscle biopsy findings. Initial therapy consisted of prednisone (1.2 to 2.9 mg/kg/day). Intravenous metho¬
trexate (approximately 1 mg/kg/wk) was added if one of the following criteria was present: (1) lack of clinical response after three months of daily corticosteroid thera¬ py, (2) rapid progression of disease leading to respiratory failure and/or substantial dysphagia, or (3) intolerable steroidinduced side effects (Table 1). With evidence of sustained improvement in muscle strength and a decrease in muscle enzymes, methotrexate therapy was grad¬ ually decreased to biweekly, triweekly, and finally, monthly doses. Patients had com-
Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/11/2015
píete blood
cell (CBC) counts done before each methotrexate injection and were observed especially for stomatitis, sore throat, purpura, fever, and gastrointestinal (GI) complaints. Measured weekly or biweekly were CPK levels (normal, 33 to 78 units/L [females] and 32 to 112 units/L [males]), SGOT levels (normal, 6 to 36 IU/L), and SGPT levels (normal, 10 to 45 IU/L). Normal serum aldolase values are 3 to 8 units/L. Urine and level of BUN were monitored periodically. Clinical improve¬ ment was also reported with serial muscle testing (using the grading system of the Medical Research Council)'- and electromyograms. All four patients were treated at UCLA; informed consent was obtained in accordance with the regulations of the UCLA Human Subjects Protection Com¬ mittee. Clinical data, response to therapy, and methotrexate dosage and toxicity are given in Tables 1, 2, and 3, respectively.
REPORT OF CASES Case 1.—An 11-year-old boy was admit¬ ted to UCLA Hospital with a seven-month history of an erythematous rash and diffuse muscle weakness and tenderness, primarily of the neck and proximal muscles of his extremities. Findings of muscle elevations, electromyogram enzyme (EMG), and muscle biopsy specimen were abnormal. An antinuclear antibody (ANA) was negative. Prednisone therapy (60 mg/ day) was started. Despite an episode of mumps encephalitis, his condition gradual¬
ly improved over eight months, requiring 40 mg of prednisone per day. At this time, bilateral-posterior subcapsular cataracts were observed. Ophthalmologic consulta¬
tion confirmed the presence of these steroid-induced cataracts and recom¬ mended immediate reduction in predni¬ sone dosage to avoid severe vision loss. Methotrexate therapy (25 mg/wk) was started in an attempt to facilitate a decrease in prednisone dosage. Over a peri-
Table 1.—Clinical Characteristics of Patients Who Received Methotrexate Initial Disease Manifestations
Creatinine/
Weight Case/ Sex
Before Methotrexate
Current
Therapy, kg
yr 16
1/M
Age
Onset,
Age,
33.4
of
yr
Proximal Muscle Weakness
Muscle
Treatment Before Methotrexate
Biopsy
Therapy
Phosphokinase
and/or Aldolase
Levels, Units/L
Rash
EMG
44/11
11
Prednisone, 40
mg/day 2/F
128/14
14.9
Prednisone, 10 mg four times per day
Indications for Methotrexate Use
Steroid-induced pos¬ terior cataracts Continued muscle weakness; marked cushingoid fea¬ tures; osteoporosis
(spine) oral and vaginal moniliasis
47.5
3/F
12
16
1,136/73
Prednisone, 15 mg four times per day
4/M
26.4
9
6,300/*
Prednisone, 15
(Patient died)
mg four times per day
Continued muscle
weakness; hyper¬ tensive
enceph¬ alopathy
Continued muscle weakness with dys¬
phagia and respira¬ tory impairment
"Not determined.
Table Duration of Methotrexate
Therapy,
2—Steroid-sparing Effect
of Methotrexate
Therapy
Proximal Muscle
Dosage
mo
Creatinine
Phosphokinase
Strength,
Prednisone
0-to-5 Scale"
EMG
and/or Aldolase Levels, Units /L
Case 1 0
40 mg
3
60 mg every other 25 mg every other 20 mg every other 20 mg every other
6 9 12
daily day day day day
4/5 5/5 5/5 5/5 5/5
14/NDt
Normal Normal Normal Normal
48/ND 30/ND
Normal
50/ND
16/11
Case 2 0 3 6 9 12
10 mg 4
times/day
30 mg every other
day 15 mg every other day 15 mg every other day 15 mg every other day
3-4/5
Abnormal
12/ND
4/5 4+/5
Improved
96/22
ND
52/14
4+/5 4+/5
Normal ND
44/9
2-3/5
Abnormal
3/5
Improved Improved
44/ND
Case 3 15 mg 4 times/day 20 mg every other day 20 mg every other day 20 mg every other day 12
3-4/5
344/7 86/ND
4/5
No
118/ND 84/ND
20 mg every other day
4/5
change Improved
148/ND
15 mg 4
Case 4
12
60 mg
times/day daily
2-3/5 3/5
25 mg 35 mg
daily daily
3/5 2/5
No
change Improved ND
2760/20 151/11 56/4
326/ND
Patient died
"Medical Research Council Grading not determined.
tND indicates
Abnormal
System.
od of 11 months he received 32 doses of methotrexate (total dose, 800 mg) with
progressive muscle-strength improvement and a decrease in steroid dose (20 mg every other day) and size of the cataracts. Methotrexate-related toxic effects included occa¬ sional transient nausea postinjection and one episode of transient elevation of SGPT
clumsiness. She could not stand or sit with¬ out support. Findings of muscle enzyme elevations, EMG, and muscle biopsy speci¬ men were characteristic of polymyositis. An ANA was negative. Prednisone, 20 mg twice daily for one month, produced
improvement. Alternate-day prednisone therapy (60 mg) for two months was asso¬
ciated with substantial deterioration of muscle strength. Despite the resumption of daily prednisone (10 mg four times a day) for four months, there was no improve¬ ment in muscle strength and substantial cushingoid features, oral and vaginal moniliasis, weight gain, and osteoporosis of the spine also developed. Intravenous metho¬ trexate therapy, 20 mg/wk, was begun. She received 39 doses over ten months (total dose, 780 mg). After three months of ther¬ apy, muscle strength and EMG substantial¬ ly improved, while prednisone dosage decreased to 30 mg every other day. Over the next nine months, while she was receiv¬ ing 15 mg of prednisone every other day, her condition remained stable. Her cushin¬ goid features improved and her weight decreased (27.5 to 23.2 kg). Except for occasional mild abdominal pain immediate¬ ly after methotrexate administration, she had no toxic reaction. At age 8 years, three years after her last dose of methotrexate, she is well while receiving prednisone (2
mg/day).
level. At 16 years of age, three years after methotrexate therapy was stopped, he has minimal muscle weakness controlled with low-dosage prednisone (10 mg every other
day).
Case 2.-A
4-year-old girl was admitted Hospital with a six-month history muscle weakness, waddling gait, and
to UCLA
of
Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/11/2015
Case 3.—A 12-year-old girl was admitted to UCLA Hospital with a four-week history
of progressive muscle weakness and heliotropic rash. Findings of physical examina¬ tion, muscle enzyme elevations (CPK, 12,960 units/mL), EMG, and muscle biopsy specimen were characteristic of dermatomyositis. An ANA was negative. Predni¬ sone (10 mg four times a day) produced
Table 3.—Methotrexate Treatment Data in Cases of
Duration, Case
Cumulative Dose, mg 800
Doses 32
Mg/kg/Dose
11
14
39
0.7-0.9
780
31
107
0.7-0.9
4,580
mo
1.3
Dermatomyositis
and
Clinical Response Steroid dose reduced; cataract size reduced; muscle strength normal¬ ized Steroid dose reduced; weight reduc¬ tion (
