Published online February 25, 2008
PEDIATRICS (doi:10.1542/peds.2007-1218)
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ARTICLE

Safety of Intravenous Immunoglobulin in the Treatment of Juvenile Dermatomyositis: Adverse Reactions Are Associated With Immunoglobulin A Content

Cedric Manlhiot, BSca, Pascal N. Tyrrell, MSca, Lisa Liang, BSca, Adelle R. Atkinson, MD, FRCPCb, Wendy Lau, MBBS, FRCP(C)c and Brian M. Feldman, MD, MSc, FRCP(C)a,d,e

a Divisions of Rheumatology
b Immunology/Allergy, Department of Pediatrics
c Division of Transfusion Medicine, Department of Pediatric Laboratory Medicine
d Department of Health Policy Management and Evaluation
e Department of Public Health Sciences, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. Anecdotal reports have suggested differences in children's tolerance to different intravenous immunoglobulin products; however, there has been little research on this issue. We sought to determine whether different intravenous immunoglobulin products used in the treatment of juvenile dermatomyositis are equally well tolerated by patients and, if not, whether differences in tolerance are linked to immunoglobulin A content.

PATIENTS AND METHODS. The intravenous immunoglobulin infusion history (product given and history of adverse events) of patients who were attending the juvenile dermatomyositis clinic at the Hospital for Sick Children from 1986 to 2005 was reviewed. Products with an immunoglobulin A content of >15 µg/mL were classified as "high immunoglobulin A." Data were analyzed by using logistic regression models adjusted for repeated measures.

RESULTS. Thirty-eight patients with juvenile dermatomyositis received 1056 infusions at the Hospital for Sick Children. Adverse events were reported on 92 occasions (9%), affecting 25 patients (66%), a frequency that is higher than that usually reported in adult patients (<1%–5%). Adverse events were reported more often with products that contained high immunoglobulin A (15.0% vs 8.0%). These were accounted for specifically by fever (8.0% vs 1.0%), lethargy or malaise (2.0% vs 0.1%), and nausea or vomiting (5.0% vs 1.0%). Of the possible pharmacologic predictors, including dose, immunoglobulin G concentration, immunoglobulin A level, pH, glycine content, sugar content, sodium content, and osmolality, only immunoglobulin A level was significantly associated with adverse events.

CONCLUSIONS. Intravenous immunoglobulin was found to be safe and well tolerated by most children with juvenile dermatomyositis. However, in contrast to adult studies, we found that significant differences existed in tolerance to different intravenous immunoglobulin products, most likely because of immunoglobulin A concentration. This study confirms anecdotal reports that a high level of immunoglobulin A in intravenous immunoglobulin is less well tolerated by children and provides evidence that product choice is important in pediatrics.

Key Words: immunoglobulin (intravenous) • IgA • drug safety • dermatomyositis (juvenile)

Abbreviations: IVIg—intravenous immunoglobulin • JDM—juvenile dermatomyositis • IgA—immunoglobulin A


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Human intravenous immunoglobulin (IVIg) transfusion was introduced in the early 1950s as a therapeutic agent for the treatment of primary and secondary immunodeficiency.1 In the past 2 decades its use has been extended; IVIg is now often used as an adjunctive therapy for juvenile dermatomyositis (JDM) and other neuromuscular disorders.2 Efficacy in the treatment of adult dermatomyositis3,4 and other adult neuromuscular disorders5,6 has already been established, and initial studies strongly suggest that IVIg is also efficacious for pediatric patients.7 IVIg is now widely used for many diseases in both adult and pediatric populations.

Although the human IgG molecule is the active agent in all IVIg products, differences in production processes have resulted in preparations with diverse pharmacologic composition.8 Questions have been raised about possible differences in efficacy and safety between the different commercial IVIgs.9 To date, most prospective trials in adult populations have found no differences in efficacy and safety between different IVIg products.10,11 These results contradict recurrent anecdotal reports of differences in the frequency of adverse events between IVIg preparations when administered to pediatric patients. However, perhaps because of the relatively low number of children receiving IVIg at any given time, the significant heterogeneity in the type of patients receiving IVIg, and the inconsistencies in product availability, long-term prospective trials evaluating IVIg tolerance in children have not been done, and these suspicions have not been formally tested.

Although IVIg infusion is considered to be a very safe treatment, adverse events, such as headaches, nausea, fever, abdominal cramps, malaise, lethargy, myalgia, and arthralgia, are commonly observed. Life-threatening reactions to IVIg are very rare but have sporadically been reported.12 Differences in preparation, mainly product concentration, sodium content, pH, and osmolality, have been hypothesized as potential risk factors for product intolerance.13 Differences in immunoglobulin A (IgA) content have not usually been considered important risk factors (except when administered to patients with IgA deficiency).

Considering our experience, IgA content may have been overlooked as a potential risk factor for IVIg tolerability. In this study we asked whether, for children with JDM, the different IVIg preparations are equally tolerated, and, if not, whether those that contain high IgA are associated with an increased frequency of adverse events.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We performed a single-center observational study of patients who were attending the JDM clinic at the Hospital for Sick Children from 1986 to 2005. The IVIg infusion history was reviewed to identify adverse events temporally associated with IVIg infusions. Some of our patients received IVIg at hospitals in their community; infusions given to these patients at external hospitals were excluded, because accurate data regarding adverse events were not available.

IVIg therapy for JDM is often given over a long course of ~2.5 years, although wide variations in treatment duration can be observed. The infusion protocol used was standardized for this population.

After research ethics board approval was obtained, blood transfusion records were obtained from the hospital pharmacy (1986–1995) and blood transfusion laboratory (1996–2005) and were cross-validated with the patient medical chart. Nursing notes for every IVIg transfusion were reviewed by an independent assessor blinded to product assignment. Adverse events were defined and classified according to the hospital "Blood Transfusion Reaction Report" (form No. 35639, December 2005 revision). Patients who developed adverse events to IVIg were often premedicated for subsequent infusions (with antihistamines and/or corticosteroids).

Patients received 1 of 4 IVIg products during the study period: Iveegam EN 5% (Baxter International Inc, Deerfield, IL), Gammagard S/D 5% (Baxter International Inc, Deerfield, IL, introduced in 1994), Gamimune N 5% (Bayer Healthcare, Research Triangle Park, NC, discontinued in 1994) and Gamimune N 10% (Bayer Healthcare, Research Triangle Park, NC, introduced in 1999). Product assignment depended on availability; however, Iveegam, when available, was preferentially used because of the suspected lower frequency of adverse reactions (based on the treating physicians’ previous experience). Each product's ingredients were obtained from the product monograph (Table 1). Iveegam (10 µg of IgA per mL) and Gammagard (2.2 µg of IgA per mL) were classified as having low IgA levels, whereas Gamimune N 5% (270 µg of IgA per mL) and Gamimune N 10% (270 µg of IgA per mL) were classified as having high IgA levels.


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  		TABLE 1 Pharmacologic Properties of IVIg Preparations (From Product Monograph)

 
Data are presented as means with SDs, medians with minimums and maximums, and frequencies, as appropriate. To account for multiple observations on each patient, univariate logistic regression models, adjusted for repeated measures using general estimating equations, were used to compare the odds of adverse events between the different IgA categories. Factors potentially affecting patient tolerance to IVIg, including age at infusion, patient IgA level, and length of treatment on IVIg, were originally included in every model to account for potential confounding but were eventually removed after they were found not to have any effect on product tolerability. Multivariable logistic regression analysis, also adjusted for repeated measures using general estimating equations, was used to determine which IVIg constituents, if any, were the most responsible for differences in adverse events between products. All of the statistical analysis was performed by using SAS 9.1 (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Over the research period, 135 patients with JDM had been followed. Of them, 47 who were either steroid resistant (had an inadequate response to corticosteroids) or steroid dependent (had a disease flare on weaning of corticosteroids) received IVIg infusions as adjunctive therapy. IVIg was used in addition to the usual "first line" treatment consisting of prednisone with or without methotrexate.14 From 1986 to 2005, 1056 infusions were given at the Hospital for Sick Children to 38 patients (Table 2). The remaining infusions (n = 521) were given in regional hospitals and, therefore, were excluded from the study. As per institutional practices, patients were screened for IgA deficiency before treatment, and no IgA-deficient patients were given IVIg.


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  		TABLE 2 Demographics

 
A total of 92 IVIg infusions (9%) in 25 (66%) of 38 patients were associated with adverse reactions, none of them life threatening. Adverse events tended to be more frequent with the initial infusion than with subsequent ones (16% vs 9%; P = .14); this is possibly because of subsequent premedication of patients who had intolerance to the first infusion.

The frequency of adverse events was not similar between IVIg preparations (Table 3). Gammagard was associated with the lowest frequency of adverse events, followed by Iveegam, and finally by Gamimune. The reactions most commonly reported were fever, headaches, nausea or vomiting, and lethargy. Arthralgia, myalgia, hives, urticaria, chills, dizziness, hypertension, back pain, chest pain, and abdominal pain were uncommonly reported.


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  		TABLE 3 IVIg Infusions, Products, and Adverse Reactions

 
Age at infusion, length of time on treatment, patient's serum IgA level at the time of infusion, and dose of IVIg given were not found to affect the frequency of adverse events. After accounting for patient individual tolerance to IVIg through repeated-measures models, we found that the incidence of adverse events was higher with "high-IgA" products; high IgA was specifically associated with increased frequency of fever, lethargy, and nausea or vomiting. Also, when accounting for within-patient variation, products with high IgA content were found to increase the odds of adverse reactions, specifically of postinfusion fever, lethargy, and nausea or vomiting (Table 4). Because of differences in the frequency of adverse events between the first and subsequent infusions, the relationship between IgA level and adverse events was also analyzed for the first infusion alone, with similar results.


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  		TABLE 4 Frequency of Adverse Reactions According to IgA Content (High Versus Low) and Univariate Odds of Adverse Events to IVIg, Adjusted for Repeated Measures

 
The influence of IVIg pharmacologic constitution on adverse events was also assessed. Infusion volume and sodium content were not included in the multivariable model because of multicollinearity with concentration. Because of the dichotomization of IgA content (low and high), multicollinearity with product pH was artificially created. Because nondichotomized product IgA content had a better fit to the data (model F value = 7.90) than pH (model F value = 7.72), pH was not included in the multivariable model. However, IgA content was used in the dichotomized form for consistency and clarity. Of product concentration, IgA level, glycine content, sugar content, and osmolality, only IgA was found to be associated with IVIg intolerance, suggesting that it is the major reason for differences in product tolerability (Table 5).


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  		TABLE 5 Odds of Adverse Reactions to IVIg According to Pharmacologic Composition, Adjusted for Repeated Measures

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study provides evidences that, for children with JDM, IVIg therapy is usually well tolerated and represents a safe option. It also confirms anecdotal reports that products with high IgA concentration are indeed associated with more adverse reactions than products with low IgA content. IgA content in IVIg seems to be associated with more adverse events, specifically with regard to fever, nausea, and lethargy. Headaches seemed not to be related to product IgA content, suggesting, perhaps, that they are reactions to the intravenous process or to other unstudied aspects of IVIg.

The frequency of adverse reactions that we observed is higher than that usually reported in adult populations (<1%–5%),15 which suggests that children may be less tolerant to IVIg than adults; however, differences in adverse event reporting cannot be ruled out. In addition, because we only studied children with JDM, it may be that some of the adverse reactions that we observed are specific for this condition (eg, it may be that patients with autoimmune diseases such as JDM, who have a hyperactive immune system, react more to exogenous IgA). Given that we observed a lower frequency of adverse events after the initial infusion, premedication of patients with initial intolerance to IVIg should be seriously considered.

In contrast to previous studies, age at infusion was not found to affect the frequency of adverse events.16 In addition, although our finding that adverse reactions are more likely on the first infusion has been reported previously, we believe that, in our cohort, it is more likely because of the premedicating of patients after the first infusion rather than reflecting habituation, as suggested previously.16 Osmolality, sodium content, and preparation concentration were not found to affect tolerance. These results differ from earlier work.17

Differences in IVIg product tolerance because of IgA content could be explained by an Fc-{alpha} receptor present on white blood cells that is activated through direct interaction with IgA. The interaction of the Fc-{alpha} receptor with IgA is a potent trigger of metabolic activation of mast cells, leading to degranulation and to superoxide release from granulocytes and monocytes.18 Mast cell degranulation leads to the release of histamine, tumor necrosis factor-{alpha}, and heparin, all of which are potent inducers of fever.19 Therefore, biological activation of IgA receptors may result in an increase of postinfusion fevers in high-IgA IVIg preparations. Children may have a higher sensitivity to immunologic triggers than adults; in the case of IVIg reactions, introduction of a relatively high dose of foreign IgA might explain why children seem to be less tolerant to IVIg than adults.

It might be argued that potential differences in IVIg product efficacy might be a more compelling reason to choose specific IVIg products rather than adverse reactions, especially when considering that adverse events were uncommon and that no life-threatening events were observed in this cohort. However, because few studies to date have found differences in IVIg product efficacy, we believe that tolerability is a reasonable guide to preparation choice.

Our results must be considered in the light of the possible limitations resulting from our study design. Our study was retrospective, and it is possible that, because of incomplete medical charts, adverse events might not have been recorded, leading to a potential underestimation of adverse events. However, the infusion protocol and patient monitoring was followed strictly, and adverse events reports were not in any way dependent on product assignment. Therefore, we believe that any underestimation introduced in our assessment would be equally distributed across products and would not affect the relationship between different products or the relationship between IgA concentration and adverse reactions.

Because most studies have not found differences in product efficacy in pediatrics, product tolerability should be the primary guideline in selecting an IVIg preparation; IVIg is often a long-term treatment, and adverse reactions to infusions can hamper patients’ quality of life. Our study suggests that, when the option is available, IVIg products with low IgA content should be selected for the treatment of children with JDM and should be considered for children with other indications.


   ACKNOWLEDGMENTS
 
Dr Feldman holds the Canada Research Chair in Childhood Arthritis. Mr Manlhiot is supported by a studentship in musculoskeletal studies granted by the Canadian Institutes of Health Research/Research and Development Research Program from the Canadian Institutes of Health Research, Institute of Musculoskeletal Health and Arthritis, and Pfizer Canada.

We acknowledge the work of Christina Goia and Derek Stephens from the Child Health Evaluative Services at the Hospital for Sick Children for advice and review of the statistical analysis, and we acknowledge Dr Brian R. Beven (Department of Pharmacy) for providing IVIg infusion records.


   FOOTNOTES
 
Accepted Aug 16, 2007.

Address correspondence to Brian M. Feldman, MD, MSc, FRCP(C), 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: brian.feldman{at}sickkids.ca

Financial Disclosure: Dr Feldman holds research grants funded by Bayer Inc; the other authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Stiehm ER. Human gamma globulins as therapeutic agents. Adv Pediatr. 1988;35 :1 –72[Medline]
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  4. Dalakas MC. High-dose intravenous immunoglobulin in inflammatory myopathies: experience based on controlled clinical trials. Neurol Sci. 2003;24 (suppl 4):S256 –S259[CrossRef][ISI][Medline]
  5. Orange JS, Hossny EM, Weiler CR, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006;117 (4 suppl):S525 –S553[CrossRef][ISI][Medline]
  6. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291 (19):2367 –2375[Abstract/Free Full Text]
  7. Al-Mayouf SM, Laxer RM, Schneider R, Silverman ED, Feldman BM. Intravenous immunoglobulin therapy for juvenile dermatomyositis: efficacy and safety. J Rheumatol. 2000;27 (10):2498 –2503[ISI][Medline]
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  9. Gelfand EW. Differences between IGIV products: impact on clinical outcome. Int Immunopharmacol. 2006;6 (4):592 –599[CrossRef][ISI][Medline]
  10. Matamoros N, De Gracia J, Hernandez F, Pons J, Alvarez A, Jimenez V. A prospective controlled crossover trial of a new presentation (10% vs. 5%) of a heat-treated intravenous immunoglobulin. Int Immunopharmacol. 2005;5 (3):619 –626[CrossRef][ISI][Medline]
  11. Schiff RI, Williams LW, Nelson RP, Buckley RH, Burks W, Good RA. Multicenter crossover comparison of the safety and efficacy of Intraglobin-F with Gamimune-N, Sandoglobulin, and Gammagard in patients with primary immunodeficiency diseases. J Clin Immunol. 1997;17 (1):21 –28[CrossRef][ISI][Medline]
  12. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Transfus Med Rev. 2003;17 (4):241 –251[CrossRef][ISI][Medline]
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




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