Identification and comparison of adverse events for preparations of IVIG in patients with neuromuscular diseases

Clinical Neurology and Neurosurgery 112 (2010) 467–469

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Identification and comparison of adverse events for preparations of IVIG in patients with neuromuscular diseases Janel O. Nadeau, Arunee Bhibhatbhan, David McDougall, Cory Toth ∗ Department of Clinical Neurosciences and the University of Calgary, Calgary, Alberta, Canada

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Article history: Received 4 May 2009 Received in revised form 15 January 2010 Accepted 16 February 2010 Available online 15 March 2010 Keywords: Chronic inflammatory demyelinating polyneuropathy Guillain-Barre syndrome Intravenous immunoglobulin Myasthenia gravis Neuromuscular disorders

a b s t r a c t Objective: Risk factors for adverse events in intravenous immunoglobulin (IVIG) therapy are uncertain. We sought to determine the associations of IVIG-related adverse events in patients with neuromuscular disorders. Patients and methods: We determined the prevalence of adverse events with the use of different forms of IVIG in a tertiary care patient population with neuromuscular diseases. A retrospective assessment for over two decades of patient care was performed. Results: Adverse events occurred in 43% of patients over time and during 10% of infusions. Prevalence of adverse events, especially headache, was higher for lyophilized forms of IVIG, and increased with cumulative IVIG delivery. Fortunately, serious adverse events were rare for all IVIG preparations. Discontinuation of IVIG therapy occurred most commonly due to perceived inefficacy or adverse events with lyophilized forms of IVIG. Conclusion: IVIG is generally well tolerated and only rarely associated with serious adverse events, but lyophilized forms of IVIG may be associated with greater prevalence of adverse events in patients with neuromuscular diseases. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Intravenous immunoglobulin (IVIG) has become an accepted therapy for the treatment of particular neurological disorders since its initial use in idiopathic thrombocytopenic purpura and immune deficiencies [1–3]. IVIG has continued to be widely used in off-label management of neuromuscular disorders [4] such as Guillain-Barre syndrome (GBS), multifocal motor neuropathy with conduction block, myasthenia gravis (MG), dermatomyositis, polymyositis, stiff person syndrome, and post-polio syndrome [1,5], and in the on-label management for chronic inflammatory demyelinating polyneuropathy (CIDP) (United States and Canada) [6] and GuillainBarre syndrome (European countries). Although many clinicians generally feel that IVIG is safe, some studies have reported rates of adverse events ranging from less than 10% of patients to up to 81% of patients [7–9]. As well, risk factors for adverse events occuring in association with IVIG are unclear and require better clarification [9]. We determined the prevalence of adverse events during IVIG use within a population of neuromuscular patients with comparison of

∗ Corresponding author at: HMRB Room 155, University of Calgary, Department of Clinical Neurosciences, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Tel.: +1 403 220 8831; fax: +1 403 283 8731. E-mail address: [email protected] (C. Toth). 0303-8467/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2010.02.008

different IVIG preparations with the intent of identifying possible risk factors for their occurrence.

2. Subjects and methods We performed a retrospective review of patients enrolled in a comprehensive tertiary clinic database at the University of Calgary Neuromuscular Clinic for the years 1988–2009. All patients with a diagnosis of possible or definite autoimmune or inflammatory neuromuscular conditions were considered. In our tertiary care centre, the delivery and characteristics of IVIG is strictly recorded for all patients prior to its delivery. In each case, the diagnosis for each patient receiving IVIG, the dose, duration and form of IVIG treatment, and the nature and prevalence of adverse events were recorded. Adverse events were obtained from standard nursing IVIG documentation form completed during therapy. Variables such as age, age at first IVIG treatment, sex, total dose of IVIG, preparation of IVIG, treatment duration and specific diagnosis were analyzed for influence upon adverse events. IVIG preparations were assessed by dividing into low (5%) and high (10–12%) concentrations and by lyophilization status. The effect of continuous variables such as age, total dose, and treatment duration on the likelihood of experiencing adverse events was determined using logistical regression. Relationships with the total number of adverse events, an integer variable, were assessed by linear

Both cumulative dosing of IVIG and the use of lyophilized forms of IVIG positively correlated with the occurrence of adverse events, while headache was more common during infusions of lyophilized IVIG as compared to liquid forms of IVIG. It is not clear why delivery of a lyophilized form of IVIG may lead to more common adverse events, as pharmacokinetic profiles appear similar between lyophilized and liquid forms [10]. It is possible that preparation errors may be more common with lyophilized forms during their reconstitution. It is unlikely that errors in preparation leading to higher concentrations of IVIG are leading to adverse events, as comparison of high to low concentrations of IVIG failed to reveal any differences in tolerability.

996 (9.8%) 10,152

4.2%

2.0%

1.6%

1.4%

0.0%

0.0%

0.1%

1/22 (5%) 0 0 0 1.9% 2.4% 2.4% 59 (14.0%) 422 ≤1 ␮g/mL

6.9%

7/202 (3%) 8/155 (5%) 0.1% 0.2% 0 0.1% 0.1% 0.1% 1.1% 1.7% 1.3% 1.7% 1.1% 2.2% 2.4% 4.3% 3156 3176 46 ␮g/mL 46 ␮g/mL

209 (6.6%) 339 (10.7%)

6/140 (4%) 0 0.1% 0 1.4% 0.3% 2.9% 174 (11%) 1536 Trace of IgA

4.0%

9/42 (21%)˝ 0.8% 0 0 1.3% 1.5% 3% 59 (14.8 %)* 400 ≤2.2 ␮g/mL

7.0%*

11/76 (15%)˝ 0 0 0 1.6% 1.4% 3.4% 12.2%* 640 <10 ␮g/mL

119 (18.6 %)*

1/7 (14%) 2/80 (3%) 0 0 1.2% 0 0 0 1.2% 1.1% 0 0.7% 2.4% 0.4% 2.4% 1.9% 6 (7.3%) 31 (4.2%) 82 740

Fever (%) Myalgia (%) Thromboembolism (%) Pruritis (%) Rash (%) HeadacheNausea (%) (%) All adverse events Adverse event Infusions

≤140 ␮g/mL 46 ␮g/mL

5% Gammagard (2007–present) 50 mg/mL; 0.25 M glycine 5% Gamimune (2001–present) 50 mg/mL; 0.2 M glycine, 100 mg/mL maltose Lyophilized 5% Iveegam 50 mg/mL; 0 glycine, 3 mg/mL (2000–2007) NaCl, 50 mg/mL glucose Lyophilized 10% Gammagard 100 mg/mL; 8.5 mg/mL NaCl, 0.3 M (2004–2007) glycine, 20 mg/mL PEG, 3 mg/mL albumin, 20 mg/mL glucose 10% pooled Cytogam 100 mg/mL; 10 mg/mL NaCl, (1988–2004) 50 mg/mL sucrose, 10 mg/mL albumin 10% Gamunex (2001–present) 100 mg/mL; 0.2 M glycine 10% Gamimune 100 mg/mL; 0.2 M glycine, (1990–present) 100 mg/mL maltose 12% Sandoglobulin 120 mg/mL; 100 mM l-isoleucine, (2006–present) 120 mM l-proline, 80 mM nicotinamide Total

4. Discussion

IgA content

A total of 580 inpatient and outpatient charts were reviewed, with IVIG provided to approximately 57% (290/512) of all patients (53% female) for the management of seven neuromuscular conditions (Appendix A). Data for the age of initiation of therapy and age at diagnosis were normally distributed. The mean age of patients at the initiation of IVIG therapy was 41.9 ± 15.1 years (range 14–85 years) and average age of diagnosis of the neuromuscular disease was 41.3 ± 15.7 years (range 13–85 years). There were 10,152 separate IVIG infusions. Routine screening for IgA deficiency was not performed. Adverse events within individual infusions were common, affecting 43% (125/290) of patients (Table 1). Headache was the most common adverse event. Instances of possible thromboembolism were rarely (1%) identified—one cerebral stroke and two pulmonary embolisms occurred within 48 h of infusion without other clinical explanations. Other adverse events occurred less commonly (Table 1). Adverse events were intolerable in 7% of patients, leading to discontinuation of therapy due to headache (15), thromboembolism (3), pruritis (2), and haemolytic anemia (1). Both logistic and linear regression identified high cumulative dosing of IVIG to directly correlate with adverse events (p < 0.01, R2 = 0.44)—this relationship was confirmed using Contingency Tables and two-tailed Fisher’s Exact Tests (p < 0.05). Using the null hypothesis that cumulative dosing of IVIG does not correlate with adverse events, Chi-Square Goodness of Fit testing concluded that we could not accept this hypothesis (p (2 ≤ critical value of 79.8) < 0.05)—cumulative dosing was related to reporting of adverse events. High or low concentrations of IVIG preparations did not influence the presence of adverse events; however, delivery of a lyophilized form of IVIG was associated with greater occurrence of overall adverse events as well as headache (p < 0.01) (Table 1). Lyophilized forms of IVIG were also associated with greater likelihood of discontinuation of use due to adverse events; the majority of overall discontinuations of a particular form of IVIG were due to inefficacy of treatment for the condition being treated or headache. A total of 22/290 (8%) of patients attempted use of ≥3 subtypes of IVIG due to perceived inefficacy of preparation or headache in most cases.

Composition

3. Results

Subtype of IVIG and years available

regression. The effect of specific variables upon adverse events was analyzed using Contingency Tables and two-tailed Fisher’s Exact Tests. Significance was set at alpha < 0.05. A normal cumulative distribution of values for statistics analyzed was performed to ensure a continuous distribution. Rates of discontinuation between groups receiving different forms of IVIG were compared with Wilcoxon Rank Sum Tests. A Chi-Square Goodness of Fit test was performed to determine if relationships with positive statistical associations had a normal distribution.

% Exposed patients discontinuing due to adverse event

J.O. Nadeau et al. / Clinical Neurology and Neurosurgery 112 (2010) 467–469 Table 1 Prevalence of specific adverse events of IVIG separated by subtype of IVIG used (organized by concentration). The years listed are those in which that subtype of IVIG was provided in our population. Greater prevalence of all or specific adverse events is indicated by * (Contingency Tables and two-tailed Fisher’s Exact Tests (p < 0.05)). Greater occurrence of IVIG subtype discontinuation is indicated by ˝ (Wilcoxon Rank Sum Test, p < 0.05).

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J.O. Nadeau et al. / Clinical Neurology and Neurosurgery 112 (2010) 467–469

The most serious and rare complication of IVIG we identified was thromboembolism. Other serious complications including aseptic meningitis, renal tubular necrosis and anaphylaxis did not occur in our population, possibly related to the absence of high osmolarity sugar stabilizers [6]. Anaphylactic reactions, described in patients with IgA deficiency [11], have been previously correlated with anti-IgA antibodies. There were no coincident cases of hepatitis, as was reported in older literature examining IVIG treatment [11]. We did not identify any cases of aseptic meningitis; patients with headaches were not found to have associated severe malaise or signs of meningismus on examination to warrant lumbar puncture studies, but milder cases of aseptic meningitis may have been overlooked. In particular, aseptic meningitis occurs most commonly in migraineurs and recurs in patients despite a switch to a different commercial preparation or with slowing the rate of IVIG infusion [12]. The nature of adverse events reported was similar to that of other studies [9,13], and headache was the most common adverse event [14]. Mechanisms by which IVIG may cause adverse events remain unclear. The development of headache syndromes with IVIG therapy may be related to IgG aggregates, IgG dimers, as well as complement activation [15]. Complement activation through aggregations of immunoglobulin molecules has also been postulated to be pathogenic for other adverse events due to IVIG [16], while thromboembolism may be related to platelet activation and arterial vasospasm [17]. Changes in the formulation of IVIG may be responsible for decreases in adverse event occurrence, with most available forms of IVIG now in liquid form and having low concentations of sugar stabilizers. The identification of lyophilization as a potential risk factor for adverse events during IVIG delivery is intriguing, and we speculate that this may relate to some degree of insolubility of portions of these preparations of IVIG. Our results are limited by their retrospective assessment, which may have contributed to underreporting. Another retrospective study has reported a higher percentage (81%) of patients experiencing adverse events [9], while a prospective efficacy study of IVIG in CIDP patients identified adverse events in 75% as compared to a rate of 21% of patients receiving placebo [6]. Assessment of individual conditions with smaller sample sizes in these studies may have further limited potential association and determination of adverse events. Variation in documentation within patient charts during different epochs of time may have limited identification of adverse events. Recognition of adverse events was limited by identification using standard nursing forms used during IVIG delivery – it was not possible to determine that all patients with no reported adverse events recorded actually had zero adverse events. Adverse events can be divided into three types: immediate adverse events (occurring during the infusion, such as with anaphylactoid reactions); delayed adverse events (occurring hours to days after initiation of infusion, such as with stroke [18]); and late adverse events (such as with transmission of infectious agents) – our analysis failed to examine for late adverse events [19]. Disparities in frequency of use between forms of IVIG were also present and related to availability over different years studied. Although our reported rates of adverse events are lower, our population was larger and followed for a greater duration. We were also unable to determine exact rates of IVIG infusion, which may relate to adverse event occurrence [20]. We advocate for standardized surveillance studies of adverse events in a population from multiple centers for improved deter-

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mination of risk factors associated with intolerability or serious adverse events with IVIG delivery. Conflicts of interest The authors have no disclosures to make regarding potential conflicts of interest. Appendix A. Neuromuscular conditions receiving IVIG Guillain-Barre syndrome (n = 155) Myasthenia gravis (n = 56) Chronic inflammatory demyelinating polyneuropathy (n = 42) Other demyelinating polyneuropathy (n = 14) Dermatomyositis (n = 9) Mononeuritis multiplex (n = 7) Polymyositis (n = 7)

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