- Email: [email protected]
Treatment of childhood dermatomyositis with high dose intravenous immunoglobulin
ELSEVIER
Treatment
,..nf
t , , The prognosis for this disorder has improved with the use of prednisone at high doses initially and then at lower
Childhood 1 IS D e r matomyos't" H i g h _D
With
ose
Intravenous s,-,,~mmuno"~ohu~n ~
Vettaikorumakankav Vedanarayanan, MD**, Sankarasubramoney H. Subramony, MD*, Linda I. Ray, MD*, and Owen B. Evans, MD**
Two children with chronic dermatomyositis who were
treated with intravenous immunoglobulin (IVIG) for 28 and 12 months, respectively, are reported. Both patients had received prednisone and immunosuppressive agents prior to IVIG treatments and had experi-
enced significant side effects. Strength and functional abilities improved in both patients in a gradual stepwise fashion with I V I G treatment. One p a t i e n t achieved remission and continues to do well without any immunosuppressive agents; in the other patient, the dose of oral steroids was reduced and other immunosuppressive agents were discontinued. Use of IVIG w a s associated with headaches, nausea, and vomiting in both patients. IVIG w a s a n useful adjuvant therapy in these 2 children with dermatomyositis without any significant side effects, Vedanarayanan V, Subramony SH, Ray LI, Evans OB. Treatment of childhood dermatomyositis with high dose intravenous immunoglobulin. Pediatr Neurol 1995;13: 336-339.
Introduction Dermatomyositis is a multisystem autoimmune disorder characterized by a typical skin rash and muscle weakness
From the Departments of *Pediatrics and *Neurology; University of Mississippi Medical Center; Jackson, Mississippi.
336
PEDIATRIC NEUROLOGY
Vol. 13 No. 4
dosages for an extended time [1,2]. The need for prolonged immunosuppression in children with chronic forms of dermatomyositis has led to the use of other immunosuppressive agents to achieve a steroid-sparing effect [3]. Azathioprine and methotrexate are currently being used in patients to achieve added immunosuppression and to reduce steroid dose [4,5]. These agents are associated with substantial side effects and require constant monitoring of hematopoietic and liver functions. Intravenous immunoglobulin (IVIG), a purified IgG fraction of human immunoglobulin, administered in high doses is useful in treating several autoimmune disorders [6], including neuromuscular disorders of autoimmune etiology [6,7]. Dalakas et al. have demonstrated that high dose IVIG is useful as an adjunctive treatment in adults with dermatomyositis [8]. We report our experience with using high dose IVIG as an adjunctive treatment in children with juvenile dermatomyositis. We treated 2 children with dermatomyositis using periodic infusions of high dose IVIG (2 gm/kg per treatment). Both children experienced improvement in strength and function over time. In 1 child complete remission was achieved and immunosuppressive treatment was successfully discontinued.
Case Reports Patient I (Fig 1, Table 1). A 7-year-old girl presented with a 2-month history of red facial rash, knee pain, and progressive muscle weakness. Her serum creatine kinase level was 1,600 U and no serologic evidence of collagen vasculardisease was present. Musclebiopsy disclosedmuscle fiber necrosis and regeneration with infiltrationof lymphocytes and mononuclear cells, predominantly in the edges of the fascicles. She was treated with prednisone at a dose of 2 mg/kg daily initially, and then with high dose Solu-Medrol pulse therapy. Azathioprine was added to prednisone at a dose of 2 mg/kg daily. Muscle strength progressively worsened and she became wheelchair bound with significant truncal weakness. As a result of steroid therapy she developed truncal obesity, candida esophagitis, and osteoporosis and suffered from a pathologic fracture of the distal femur. One course of plasmapheresis (consisting of 250 ml/kg total plasma volume exchanged) was performed, and she developed femoral vein thrombosis from the catheter used for the treatment. No improvement was detected after plasmapheresis and treatments were discontinued. IVIG treatments were begun 2 years after onset of the disease and she initially received infusions once every month and then once every 2-4 months. After three courses of treatment muscle strength began to improve. The erythematous rash on her face and over the knuckles, as well as the areas of calcinosis, resolved. She received IVIG treatments for 28 months, after which she could walk with long leg braces and a walker.
Communications should be addressed to: Dr. Vedanarayanan; Division of Pediatric Neurology; University of Mississippi Medical Center; Jackson, MS 39216. Received June 9, 1995; accepted August 31, 1995.
© 1995 by Elsevier Science Inc. • 0887-8994/95/$9.50 SSDI 0887-8994(95)00195-6
CK 66 IU 1
CK/ 16001U Skin rash
T
Rash Candida
Complications
Femoral vein
Oesophagitis
Treatment I
Rash resolved
ll--*~o--o--e~o--e-e
Thrombosis
.... Azathioprine
[
,H~AV///J<]---~Plasmapheresis IVIG I
I
Steroids
J Figure I. Functional status on modified Rankin scale (Table 1), treatment given, and complications experienced by Patient 1 over 54month follow-up period. CK = Creatine kinase, IVIG = intravenous immunoglobulin.
Release of 0
contractures
1
-o~ .~_ 09
2
5
t
I
I
I
I
!
0
12
24
36
48
60
Months She experienced frontal headaches and vomiting during IVIG infusions and was managed symptomatically, Patient 2 (Fig 2). A 2-year-old girl presented with a rash on face, knuckles, and knees and with inability to run, climb, or jump. On examination she had moderately severe weakness of her proximal muscles in the upper and lower limbs. Her serum creatinine kinase level was elevated (2,200 IU), and an open muscle biopsy disclosed typical changes of dermatomyositis. She was treated with daily prednisone for 1 year and manifested some improvement in strength. She developed osteoporosis and developed asymptomatic collapse of two lumbar vertebral bodies. The dose of prednisone was incrementally discontinued. Weekly methotrexate therapy was initiated and motor strength and function improved. She could perform normal activities of daily living; however, she could not run, jump, or climb. She was treated with methotrexate for 3.5
Table l.
Modified Rankin scale for assessment of disability*
1. No significant disability despite symptoms: able to carry out all usual duties and activities, 2. Slight disability: unable to carry out all previous activities but able to look after own affairs without assistance. 3. Moderate disability: requiring some help, but able to walk without assistance, 4. Moderately severe disability: unable to walk without assistance, and unable to attend to own bodily needs without assistance, 5. Severe disability: bedridden, incontinent, and requiring constant nursing care and attention, * Reproduced with permission from Van Swieten et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604-7, ©1988 American Heart Association.
years and reached the maximum cumulative dose of 2,000 mg. Periodic infusions of IVIG were initiated, first once every 4 weeks and then at gradually increasing intervals. Methotrexate therapy was discontinued incrementally. She responded with further improvement in strength and motor function. Six months after initiation of the IVIG treatments she was able to run, hop on her toes, and jump, which she had not been able to do since the onset of the illness. At the last examination, which was performed 6 months after discontinuing IVIG treatment, she continued to maintain normal muscle strength and function. She experienced headaches and vomiting during and for few days after the IVIG infusions.
Discussion We report our experience with using high dose IVIG in treating 2 children with dermatomyositis who had suboptimal response to treatment with prednisone and cytotoxic agents. Both children manifested an improvement in their strength and functional ability (measured on modified Rankin scale [9]), and resolution of their skin rash. T h e response to IVIG was slow and was observed to o c c u r in a stepwise fashion after a few courses of treatment. The response was different from that reported after t r e a t m e n t of other autoimmune disorders (e.g. demyelinating polyneuropathies [ 10,11 ], idiopathic thrombocytopenia [6]), which respond rapidly to infusion of intravenous immunoglobulin. Neither patient experienced serious side efduring or after treatment with high dose IVIG. The clinical course of dermatomyositis is variable. In
fects
Vedanarayanan et al: Intravenous Immunoglobulin in Dermatomyositis
337
CK-2,2OOIU / Skin rash
'l
CK 99 IU
/
Skin rash
I Rash resolved
Osteoporosis vertebral collapse
Complications
Treatment-I
Steroids
t[
Elevated transaminases
Weeklmethotrexate )'
j
IVIG . j
0
Figure 2. Functional status on modified Rankin scale (Table 1), treatment given, and complications experienced by Patient 2 over 72month follow-up period.
1
~09 "0 ¢0".~ rr
3
)
G
¢-
4 5
I 0
t 12
I 24
I 36
I 48
I 60
I 72
Months
adults the course is one of gradual progression of weakness if left untreated. In the absence of malignancy, 7089% survive for a 5-year period and - 3 3 % achieve remission with immunosuppressive therapy [1]. Spencer et al. reported three temporal patterns of progression of this disease in children [2]. In their series of patients, about one-third had a monocyclic course, usually lasting several months. Ten of their 32 children with dermatomyositis had a chronic polycyclic course with relapses occurring during gradual withdrawal of steroids and 14 children had a chronic and progressive course with continued progression in motor disability. The mean duration of corticosteroid treatment in the chronic form of dermatomyositis was 50-55 months [2]. Both our patients had a chronic form of dermatomyositis with illness lasting for 5 and 6 years, respectively. The use of IVIG treatments as an adjunctive treatment in these children enabled us to decrease the dose of immunosuppressive agents in 1 patient and discontinue it in the other. In Patient 1 the dose of prednisone was reduced and azathioprine discontinued. In Patient 2 the weekly methotrexate treatments were discontinued without any worsening of muscle strength, Lang et al. reported improved strength in 5 children with dermatomyositis who were treated with IVIG. The dose of corticosteroid was reduced in 3 patients and discontinued in 2 [12]. Dalakas et al. reported improvement in strength and neuromuscular function in 14 of 15 patients with dermatomyositis who did not respond to the conventional therapy in a double-blind placebo-controlled crossover study using IVIG. In addition to improvement in strength and function, the histologic and immunopatho-
338
PEDIATRIC NEUROLOGY
Vol. 13 No. 4
logic findings in muscle biopsies performed before and after IVIG treatment disclosed reduction in inflammation [8]. IVIG treatment is generally associated with relatively minor side effects. Headaches, nausea, low grade fever, and vomiting are the most frequently encountered problems. Both our children experienced similar side effects with IVIG treatments. Vascular complications involving the central nervous system, heart, and kidneys [13,14] have not been encountered in children treated with IVIG, but transmission of infectious agents is a concern. A1though there are no reports of transmission of HIV or hepatitis B virus, transmission of hepatitis C virus through IVIG infusion has been reported [15]. The mechanism by which IVIG exerts a therapeutic effect in dermatomyositis is unclear. Blockade of Fc receptors on the endothelial surface of capillaries by high dose IVIG, thereby preventing the complement-mediated injury to blood vessels and muscle fibers, seems to be the important mechanism in producing the therapeutic effect [16-18]. IVIG may also neutralize complement neoantigens formed during activation of complement pathway and inhibit formation of membrane attack complex [19]. Basta and Dalakas have demonstrated that the beneficial effect of IVIG treatments in patients with dermatomyositis is mediated through blocking of formation and deposition of activated complement fragments in the endomysial blood vessels [20]. Inhibition of effector function of T-cells through release of cytokines and adhesion molecules may also be modified by IVIG in dermatomyositis [8].
The efficacy of IVIG is short lived and multiple infusions are required for a lasting benefit. Our patients m a n ifested slow incremental improvement with each treatmerit, and required many treatments before significant iraprovement in strength was observed. The benefit of reducing steroid dosage with IVIG treatments is a major advantage in reducing the morbidity associated with longt e r m high-dose steroid use. The cost of these treatments is
high; however, the improved safety and tolerance of IVIG o v e r corticosteroid and other immunosuppressive agents are its major advantages as a steroid-sparing therapy. The authors thank Dr. Arturo A. Leis for reviewing the manuscript and offering helpful suggestions, and Louellen R. Smith and Anita R. Stevens for assistance in manuscript preparation.
References [1] Engel AG, Hohfeld H, Banker BQ, The polymyositis and dermatomyositis syndromes. In: Engel AG, Franzini-Armstrong, eds. Myology. 2rid ed. New York: McGraw Hill, 1994:1335-83. [2] Spencer CH, Hanson V, Singsen BH, Bernstein BH, Komreich HK, King KK. Course of treated juvenile dermatomyositis. J Pediatr 1984;105:399-408. [3] Dubowitz V. Treatment of dermatomyositis in childhood. Arch Dis Child 1976;51:494-500. [4] Jacobs JC. Methotrexate and azathioprine treatment of childhood dermatomyositis. Pediatrics 1977;59:212-8. [5] Niakam E, Pitner SE, Whitaker JN, Bertolini TE. Immunosuppressive agents in corticosteroid refractory childhood dermatomyositis. Neurology 1980;30:286-9 I. [6] Dwyer J. Manipulating the immune system with immune globulin. N Engl J Med 1992;326:107-16. [7] Soueidan SA, Dalakas MC. Treatment of autoimmune neuromuscular diseases with high dose intravenous immune globulin. Pediatr Res 1993;33:$95-100. [8] Dalakas MC, Illa I, Damhrosia JM, et al. A controlled trial of high dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329:1993-2000.
191 Van Swieten JC, KoudstallJ, Visser MC, SchoutenHJA, Van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604-7. [10] Vedanarayanan VV, Kandt RS, Lewis DV, Delong GR. Chronic inflammatory deymelinating polyradiculoneuropathy of childhood; treatmentwith high dose intravenousimmunoglobulin. Neurology
1991;41:828-30. [11] Van der Merehe FGA, Schmitz PIM, the Dutch Guillian Barre Study Group 1992. A randomized trial comparing intravenous immunoglobulin and plasma exchange in Guillian Barre syndrome. N Engl J Med 1992;326:1123-9+ [12] Lang BA, Laxere RM, Murphy G, Silverman El3, Roifman CN. Treatment of dermatomyositis with intravenous gammaglobulin. Am J Med 1991;91:169-72. [13] Canter TG, Hoeh-Sonic EW, Burgess JM, Raevsen L, Sheck PJ. Acute renal failure associated with immunoglobulin therapy. Am J Kidney Dis 1995;25:228-34. [14] Steg RE, Lefkowitz DM. Cerebral infarction following intravenous immunoglobulin therapy for myasthenia gravis. Neurology 1994; 44:1180-1. [15] Outbreak of hepatitis C associated with intravenous immunoglobulin administration--United States, October 1993-June 1994. MMWR 1994;43(28):505-9. [16] Whitaker JN, Engel WK. Vascular deposits of immunoglobulin and complement in idiopathic inflammatory myopathy. N Engl J Med 1972;286:333-8. [17] Kissel JT, Mendell JR, Rammohan KW. Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 1986;314:329-34. [18] Enger AG, Biesecker G. Complement activation in muscle fiber necrosis. Demonstration of the membrane attack complex of complement in necrotic fibers. Ann Neurol 1982;12:289-96. [19] Basta M, Kiesbom P, Frank MM, Fres LF. Mechanism of therapeutic effect of high dose intravenous immunoglobulin. Attenuation of acute complement dependent immune damage in guinea pig model. J Clin Invest 1989;84:1974-81. [20] Basta M, Dalakas MC. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J Clin Invest 1994;94:1729-35.
Vedanarayanan et al: Intravenous Immunoglobulin in Dermatomyositis
339
Treatment
,..nf
t , , The prognosis for this disorder has improved with the use of prednisone at high doses initially and then at lower
Childhood 1 IS D e r matomyos't" H i g h _D
With
ose
Intravenous s,-,,~mmuno"~ohu~n ~
Vettaikorumakankav Vedanarayanan, MD**, Sankarasubramoney H. Subramony, MD*, Linda I. Ray, MD*, and Owen B. Evans, MD**
Two children with chronic dermatomyositis who were
treated with intravenous immunoglobulin (IVIG) for 28 and 12 months, respectively, are reported. Both patients had received prednisone and immunosuppressive agents prior to IVIG treatments and had experi-
enced significant side effects. Strength and functional abilities improved in both patients in a gradual stepwise fashion with I V I G treatment. One p a t i e n t achieved remission and continues to do well without any immunosuppressive agents; in the other patient, the dose of oral steroids was reduced and other immunosuppressive agents were discontinued. Use of IVIG w a s associated with headaches, nausea, and vomiting in both patients. IVIG w a s a n useful adjuvant therapy in these 2 children with dermatomyositis without any significant side effects, Vedanarayanan V, Subramony SH, Ray LI, Evans OB. Treatment of childhood dermatomyositis with high dose intravenous immunoglobulin. Pediatr Neurol 1995;13: 336-339.
Introduction Dermatomyositis is a multisystem autoimmune disorder characterized by a typical skin rash and muscle weakness
From the Departments of *Pediatrics and *Neurology; University of Mississippi Medical Center; Jackson, Mississippi.
336
PEDIATRIC NEUROLOGY
Vol. 13 No. 4
dosages for an extended time [1,2]. The need for prolonged immunosuppression in children with chronic forms of dermatomyositis has led to the use of other immunosuppressive agents to achieve a steroid-sparing effect [3]. Azathioprine and methotrexate are currently being used in patients to achieve added immunosuppression and to reduce steroid dose [4,5]. These agents are associated with substantial side effects and require constant monitoring of hematopoietic and liver functions. Intravenous immunoglobulin (IVIG), a purified IgG fraction of human immunoglobulin, administered in high doses is useful in treating several autoimmune disorders [6], including neuromuscular disorders of autoimmune etiology [6,7]. Dalakas et al. have demonstrated that high dose IVIG is useful as an adjunctive treatment in adults with dermatomyositis [8]. We report our experience with using high dose IVIG as an adjunctive treatment in children with juvenile dermatomyositis. We treated 2 children with dermatomyositis using periodic infusions of high dose IVIG (2 gm/kg per treatment). Both children experienced improvement in strength and function over time. In 1 child complete remission was achieved and immunosuppressive treatment was successfully discontinued.
Case Reports Patient I (Fig 1, Table 1). A 7-year-old girl presented with a 2-month history of red facial rash, knee pain, and progressive muscle weakness. Her serum creatine kinase level was 1,600 U and no serologic evidence of collagen vasculardisease was present. Musclebiopsy disclosedmuscle fiber necrosis and regeneration with infiltrationof lymphocytes and mononuclear cells, predominantly in the edges of the fascicles. She was treated with prednisone at a dose of 2 mg/kg daily initially, and then with high dose Solu-Medrol pulse therapy. Azathioprine was added to prednisone at a dose of 2 mg/kg daily. Muscle strength progressively worsened and she became wheelchair bound with significant truncal weakness. As a result of steroid therapy she developed truncal obesity, candida esophagitis, and osteoporosis and suffered from a pathologic fracture of the distal femur. One course of plasmapheresis (consisting of 250 ml/kg total plasma volume exchanged) was performed, and she developed femoral vein thrombosis from the catheter used for the treatment. No improvement was detected after plasmapheresis and treatments were discontinued. IVIG treatments were begun 2 years after onset of the disease and she initially received infusions once every month and then once every 2-4 months. After three courses of treatment muscle strength began to improve. The erythematous rash on her face and over the knuckles, as well as the areas of calcinosis, resolved. She received IVIG treatments for 28 months, after which she could walk with long leg braces and a walker.
Communications should be addressed to: Dr. Vedanarayanan; Division of Pediatric Neurology; University of Mississippi Medical Center; Jackson, MS 39216. Received June 9, 1995; accepted August 31, 1995.
© 1995 by Elsevier Science Inc. • 0887-8994/95/$9.50 SSDI 0887-8994(95)00195-6
CK 66 IU 1
CK/ 16001U Skin rash
T
Rash Candida
Complications
Femoral vein
Oesophagitis
Treatment I
Rash resolved
ll--*~o--o--e~o--e-e
Thrombosis
.... Azathioprine
[
,H~AV///J<]---~Plasmapheresis IVIG I
I
Steroids
J Figure I. Functional status on modified Rankin scale (Table 1), treatment given, and complications experienced by Patient 1 over 54month follow-up period. CK = Creatine kinase, IVIG = intravenous immunoglobulin.
Release of 0
contractures
1
-o~ .~_ 09
2
5
t
I
I
I
I
!
0
12
24
36
48
60
Months She experienced frontal headaches and vomiting during IVIG infusions and was managed symptomatically, Patient 2 (Fig 2). A 2-year-old girl presented with a rash on face, knuckles, and knees and with inability to run, climb, or jump. On examination she had moderately severe weakness of her proximal muscles in the upper and lower limbs. Her serum creatinine kinase level was elevated (2,200 IU), and an open muscle biopsy disclosed typical changes of dermatomyositis. She was treated with daily prednisone for 1 year and manifested some improvement in strength. She developed osteoporosis and developed asymptomatic collapse of two lumbar vertebral bodies. The dose of prednisone was incrementally discontinued. Weekly methotrexate therapy was initiated and motor strength and function improved. She could perform normal activities of daily living; however, she could not run, jump, or climb. She was treated with methotrexate for 3.5
Table l.
Modified Rankin scale for assessment of disability*
1. No significant disability despite symptoms: able to carry out all usual duties and activities, 2. Slight disability: unable to carry out all previous activities but able to look after own affairs without assistance. 3. Moderate disability: requiring some help, but able to walk without assistance, 4. Moderately severe disability: unable to walk without assistance, and unable to attend to own bodily needs without assistance, 5. Severe disability: bedridden, incontinent, and requiring constant nursing care and attention, * Reproduced with permission from Van Swieten et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604-7, ©1988 American Heart Association.
years and reached the maximum cumulative dose of 2,000 mg. Periodic infusions of IVIG were initiated, first once every 4 weeks and then at gradually increasing intervals. Methotrexate therapy was discontinued incrementally. She responded with further improvement in strength and motor function. Six months after initiation of the IVIG treatments she was able to run, hop on her toes, and jump, which she had not been able to do since the onset of the illness. At the last examination, which was performed 6 months after discontinuing IVIG treatment, she continued to maintain normal muscle strength and function. She experienced headaches and vomiting during and for few days after the IVIG infusions.
Discussion We report our experience with using high dose IVIG in treating 2 children with dermatomyositis who had suboptimal response to treatment with prednisone and cytotoxic agents. Both children manifested an improvement in their strength and functional ability (measured on modified Rankin scale [9]), and resolution of their skin rash. T h e response to IVIG was slow and was observed to o c c u r in a stepwise fashion after a few courses of treatment. The response was different from that reported after t r e a t m e n t of other autoimmune disorders (e.g. demyelinating polyneuropathies [ 10,11 ], idiopathic thrombocytopenia [6]), which respond rapidly to infusion of intravenous immunoglobulin. Neither patient experienced serious side efduring or after treatment with high dose IVIG. The clinical course of dermatomyositis is variable. In
fects
Vedanarayanan et al: Intravenous Immunoglobulin in Dermatomyositis
337
CK-2,2OOIU / Skin rash
'l
CK 99 IU
/
Skin rash
I Rash resolved
Osteoporosis vertebral collapse
Complications
Treatment-I
Steroids
t[
Elevated transaminases
Weeklmethotrexate )'
j
IVIG . j
0
Figure 2. Functional status on modified Rankin scale (Table 1), treatment given, and complications experienced by Patient 2 over 72month follow-up period.
1
~09 "0 ¢0".~ rr
3
)
G
¢-
4 5
I 0
t 12
I 24
I 36
I 48
I 60
I 72
Months
adults the course is one of gradual progression of weakness if left untreated. In the absence of malignancy, 7089% survive for a 5-year period and - 3 3 % achieve remission with immunosuppressive therapy [1]. Spencer et al. reported three temporal patterns of progression of this disease in children [2]. In their series of patients, about one-third had a monocyclic course, usually lasting several months. Ten of their 32 children with dermatomyositis had a chronic polycyclic course with relapses occurring during gradual withdrawal of steroids and 14 children had a chronic and progressive course with continued progression in motor disability. The mean duration of corticosteroid treatment in the chronic form of dermatomyositis was 50-55 months [2]. Both our patients had a chronic form of dermatomyositis with illness lasting for 5 and 6 years, respectively. The use of IVIG treatments as an adjunctive treatment in these children enabled us to decrease the dose of immunosuppressive agents in 1 patient and discontinue it in the other. In Patient 1 the dose of prednisone was reduced and azathioprine discontinued. In Patient 2 the weekly methotrexate treatments were discontinued without any worsening of muscle strength, Lang et al. reported improved strength in 5 children with dermatomyositis who were treated with IVIG. The dose of corticosteroid was reduced in 3 patients and discontinued in 2 [12]. Dalakas et al. reported improvement in strength and neuromuscular function in 14 of 15 patients with dermatomyositis who did not respond to the conventional therapy in a double-blind placebo-controlled crossover study using IVIG. In addition to improvement in strength and function, the histologic and immunopatho-
338
PEDIATRIC NEUROLOGY
Vol. 13 No. 4
logic findings in muscle biopsies performed before and after IVIG treatment disclosed reduction in inflammation [8]. IVIG treatment is generally associated with relatively minor side effects. Headaches, nausea, low grade fever, and vomiting are the most frequently encountered problems. Both our children experienced similar side effects with IVIG treatments. Vascular complications involving the central nervous system, heart, and kidneys [13,14] have not been encountered in children treated with IVIG, but transmission of infectious agents is a concern. A1though there are no reports of transmission of HIV or hepatitis B virus, transmission of hepatitis C virus through IVIG infusion has been reported [15]. The mechanism by which IVIG exerts a therapeutic effect in dermatomyositis is unclear. Blockade of Fc receptors on the endothelial surface of capillaries by high dose IVIG, thereby preventing the complement-mediated injury to blood vessels and muscle fibers, seems to be the important mechanism in producing the therapeutic effect [16-18]. IVIG may also neutralize complement neoantigens formed during activation of complement pathway and inhibit formation of membrane attack complex [19]. Basta and Dalakas have demonstrated that the beneficial effect of IVIG treatments in patients with dermatomyositis is mediated through blocking of formation and deposition of activated complement fragments in the endomysial blood vessels [20]. Inhibition of effector function of T-cells through release of cytokines and adhesion molecules may also be modified by IVIG in dermatomyositis [8].
The efficacy of IVIG is short lived and multiple infusions are required for a lasting benefit. Our patients m a n ifested slow incremental improvement with each treatmerit, and required many treatments before significant iraprovement in strength was observed. The benefit of reducing steroid dosage with IVIG treatments is a major advantage in reducing the morbidity associated with longt e r m high-dose steroid use. The cost of these treatments is
high; however, the improved safety and tolerance of IVIG o v e r corticosteroid and other immunosuppressive agents are its major advantages as a steroid-sparing therapy. The authors thank Dr. Arturo A. Leis for reviewing the manuscript and offering helpful suggestions, and Louellen R. Smith and Anita R. Stevens for assistance in manuscript preparation.
References [1] Engel AG, Hohfeld H, Banker BQ, The polymyositis and dermatomyositis syndromes. In: Engel AG, Franzini-Armstrong, eds. Myology. 2rid ed. New York: McGraw Hill, 1994:1335-83. [2] Spencer CH, Hanson V, Singsen BH, Bernstein BH, Komreich HK, King KK. Course of treated juvenile dermatomyositis. J Pediatr 1984;105:399-408. [3] Dubowitz V. Treatment of dermatomyositis in childhood. Arch Dis Child 1976;51:494-500. [4] Jacobs JC. Methotrexate and azathioprine treatment of childhood dermatomyositis. Pediatrics 1977;59:212-8. [5] Niakam E, Pitner SE, Whitaker JN, Bertolini TE. Immunosuppressive agents in corticosteroid refractory childhood dermatomyositis. Neurology 1980;30:286-9 I. [6] Dwyer J. Manipulating the immune system with immune globulin. N Engl J Med 1992;326:107-16. [7] Soueidan SA, Dalakas MC. Treatment of autoimmune neuromuscular diseases with high dose intravenous immune globulin. Pediatr Res 1993;33:$95-100. [8] Dalakas MC, Illa I, Damhrosia JM, et al. A controlled trial of high dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329:1993-2000.
191 Van Swieten JC, KoudstallJ, Visser MC, SchoutenHJA, Van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604-7. [10] Vedanarayanan VV, Kandt RS, Lewis DV, Delong GR. Chronic inflammatory deymelinating polyradiculoneuropathy of childhood; treatmentwith high dose intravenousimmunoglobulin. Neurology
1991;41:828-30. [11] Van der Merehe FGA, Schmitz PIM, the Dutch Guillian Barre Study Group 1992. A randomized trial comparing intravenous immunoglobulin and plasma exchange in Guillian Barre syndrome. N Engl J Med 1992;326:1123-9+ [12] Lang BA, Laxere RM, Murphy G, Silverman El3, Roifman CN. Treatment of dermatomyositis with intravenous gammaglobulin. Am J Med 1991;91:169-72. [13] Canter TG, Hoeh-Sonic EW, Burgess JM, Raevsen L, Sheck PJ. Acute renal failure associated with immunoglobulin therapy. Am J Kidney Dis 1995;25:228-34. [14] Steg RE, Lefkowitz DM. Cerebral infarction following intravenous immunoglobulin therapy for myasthenia gravis. Neurology 1994; 44:1180-1. [15] Outbreak of hepatitis C associated with intravenous immunoglobulin administration--United States, October 1993-June 1994. MMWR 1994;43(28):505-9. [16] Whitaker JN, Engel WK. Vascular deposits of immunoglobulin and complement in idiopathic inflammatory myopathy. N Engl J Med 1972;286:333-8. [17] Kissel JT, Mendell JR, Rammohan KW. Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 1986;314:329-34. [18] Enger AG, Biesecker G. Complement activation in muscle fiber necrosis. Demonstration of the membrane attack complex of complement in necrotic fibers. Ann Neurol 1982;12:289-96. [19] Basta M, Kiesbom P, Frank MM, Fres LF. Mechanism of therapeutic effect of high dose intravenous immunoglobulin. Attenuation of acute complement dependent immune damage in guinea pig model. J Clin Invest 1989;84:1974-81. [20] Basta M, Dalakas MC. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J Clin Invest 1994;94:1729-35.
Vedanarayanan et al: Intravenous Immunoglobulin in Dermatomyositis
339