Background
Dermatomyositis is an idiopathic inflammatory myopathy characterised by rashes and progressive muscle weakness [
1]. It is estimated to affect between 1 and 13 people per 100,000 of the US population [
2,
3]. Although the pathogenesis of dermatomyositis is unknown, several genetic, immunologic and environmental factors have been implicated [
4].
Glucocorticoids and other immunosuppressive drugs are widely used in the treatment of dermatomyositis but are often associated with significant adverse effects. In addition, patients with myositis have a high rate of mortality due to infections [
5,
6]. Intravenous immunoglobulins (IVIg) are highly purified immunoglobulin G concentrates prepared from human plasma and are widely used in the treatment of autoimmune and inflammatory disorders [
7,
8]. IVIg is recommended in European guidelines as a glucocorticoid-sparing agent and is used off-label for dermatomyositis, usually in combination with immunosuppressive drugs [
9‐
11]. However, there has been a lack of large, randomised studies to support the use of IVIg in this patient population.
The ProDERM (Progress in DERMatomyositis) study recently established the efficacy, safety and tolerability of IVIg in adult dermatomyositis patients in a large, randomised, placebo-controlled trial [
12,
13]. The study showed that significantly more patients responded to IVIg than placebo (78.7% versus 43.8%, respectively). The results of the ProDERM study led to the approval of IVIg (Octagam 10%) for treatment of dermatomyositis in the USA, Canada and most European countries [
14‐
16].
Here, we present detailed analyses of the safety and tolerability of IVIg in patients with dermatomyositis from the ProDERM study.
Results
Patient demographics and baseline characteristics
Of 126 patients screened, 95 were enrolled in the study, with 47 randomised in the first period to receive IVIg and 48 randomised to receive placebo. All enrolled patients received at least one infusion of study drug and were thus included in the safety analysis set and analysed according to the intention-to-treat principle. Of patients randomised to receive IVIg, 45 (95.7%) completed the first period, as did 46 (95.8%) in the placebo group. Five patients (10.4%) on placebo crossed over to IVIg during the first period, with no patients on IVIg switching to placebo. A total of 69 (72.6%) patients completed the extension period. Full details of patient disposition were described by Aggarwal et al. (2022) [
12].
Demographics and baseline characteristics were generally balanced between groups [
12]. Briefly, the median (range) age was 52.0 years (22.0–79.0), and 71 (74.7%) patients were female. Median time since diagnosis was 2.6 years (0.1–48.7). All patients exhibited symmetric proximal muscle weakness and typical skin rash, with a mean MMT-8 score of 120.9 (maximum 150), and 67 patients (70.5%) had dermatomyositis classed as ‘definite’. The use of concomitant therapy was similar between the two treatment groups, with glucocorticoids taken by 88.4% of patients and non-glucocorticoid medications taken by 68.4%.
During the study, 664 infusion cycles were administered, with a median dose of 2.0 g/kg IVIg. The median duration of infusion cycles was 2.4 days, with 76 (80.0%) patients receiving IVIg over ≤ 2 days. A total of 33 (34.7%) patients had IVIg infusion cycles over 3 days, 12 (12.6%) patients received IVIg over 4 days and 2 (2.1%) patients received IVIg infusions over 5 days (some patients received IVIg over more than one duration).
Overview of adverse events
A summary of adverse events experienced during the study is presented in Table
1. All adverse events were deemed to be TEAEs.
Table 1
Overview of adverse events
TEAEs | 42 (80.8%) | 196 | 28 (58.3%) | 135 | 84 (88.4%) | 545 |
Infusional TEAEs | 34 (65.4%) | 139 | 19 (39.6%) | 65 | 76 (80.0%) | 351 |
Serious TEAEs | 3 (5.8%) | 5 | 2 (4.2%) | 4 | 14 (14.7%) | 22 |
TEAEs related to study drug | 30 (57.7%) | 113 | 11 (22.9%) | 38 | 62 (65.3%) | 282 |
TEAEs leading to discontinuation of study drug | 3 (5.8%) | 8 | 0 (0.0%) | 0 | 13 (13.7%) | 25 |
TEEs | 1 (1.9%) | 2 | 0 (0.0%) | 0 | 6 (6.3%) | 8 |
Relatedb TEEs | 0 (0.0%) | 0 | 0 (0.0%) | 0 | 5 (5.3%) | 6 |
HTRs | 0 (0.0%) | 0 | 0 (0.0%) | 0 | 0 (0.0%) | 0 |
Deaths | 0 (0.0%) | 0 | 0 (0.0%) | 0 | 0 (0.0%) | 0 |
During the first period, 42 patients (80.8%) who received IVIg experienced a total of 196 TEAEs and 28 patients (58.3%) who received placebo experienced 135 TEAEs (Table
1). Of these, there were 113 treatment-related TEAEs in 30 patients (57.7%) in the IVIg group and 38 related TEAEs in 11 patients (22.9%) in the placebo group.
In the overall period, 84 patients (88.4%) experienced 545 TEAEs following treatment with IVIg (Table
1). Of these, 282 TEAEs in 62 patients (65.3%) were assessed as related to the study drug (Suppl. Table
1). Most of these related TEAEs (260/282; 92.20%) occurred during or within 72 h of an infusion cycle and were classed as infusional TEAEs, whereas in the placebo group, 29/38 (76.32%) were classed as infusional TEAEs. The most commonly reported IVIg-related TEAEs (> 5% of patients) were headache (42%), fever (19%), nausea (16%), vomiting (8%), chills (7%), musculoskeletal pain (7%) and increased blood pressure (6%) (Suppl. Table
1). Of the patients who received infusions over ≤ 2 days, 42 (54.6%) experienced a related TEAE compared with 27 patients (71.1%) who received infusions over > 2 days (most likely due to patients having their infusion cycles lengthened due to such side effects).
Adverse events stratified by intensity and seriousness
Most TEAEs experienced during the study were deemed related to the study drug and were mild in intensity. In the first period, for patients who received IVIg, 82 of 113 related TEAEs were mild, 28 were moderate and 3 were classed as severe (Table
2). In patients who received placebo, 24 mild, 14 moderate, and no severe related TEAEs occurred. The pattern of TEAE intensity with IVIg was similar in the overall period to that seen in the first period; for the overall period, 207 of 282 related TEAEs were classed as mild in intensity, 66 were classed as moderate and 9 were classed as severe. The nine TEAEs of severe intensity were experienced by a total of five patients and included four events of headache and one event each of nausea, muscle spasms, dyspnoea, DVT and PE.
Table 2
TEAEs by intensity in the first period and overall period
All TEAEs |
Mild | 39 (75.0%) | 142 (72.4%) | 28 (58.3%) | 102 (75.6%) | 79 (83.2%) | 405 (74.3%) |
Moderate | 20 (38.5%) | 48 (24.5%) | 10 (20.8%) | 33 (24.4%) | 39 (41.1%) | 118 (21.7%) |
Severe | 4 (7.7%) | 6 (3.1%) | 0 (0.0%) | 0 (0.0%) | 10 (10.5%) | 22 (4.0%) |
TEAEs relatedb to study drug |
Mild | 28 (53.8%) | 82 (72.6%) | 9 (18.8%) | 24 (63.2%) | 55 (57.9%) | 207 (73.4%) |
Moderate | 13 (25.0%) | 28 (24.8%) | 5 (10.4%) | 14 (36.8%) | 25 (26.3%) | 66 (23.4%) |
Severe | 2 (3.8%) | 3 (2.7%) | 0 (0.0%) | 0 (0.0%) | 5 (5.3%) | 9 (3.2%) |
The latency time and duration for the related TEAEs of headache, nausea, vomiting and fever during the first period are presented in Table
3. In patients who received IVIg, both median latency times and durations for each of the related TEAEs were rather short, ranging from 0 to 3 days, and generally, the latency times and durations of these TEAEs were similar between the IVIg and placebo groups. Latency time and duration of the TEAEs did not appear to change with severity of the TEAE.
Table 3
Latency and duration of the related TEAEs of headache, nausea, vomiting and fever stratified by severity (first period)
Headache |
Mild | 32 | 0.5 (0.0–4.0) | 3 | 0.0 (0.0–14.0) | 32 | 1.0 (1.0–5.0) | 2 | 8.0 (1.0–15.0) |
Moderate | 12 | 2.0 (0.0–4.0) | 4 | 0.0 (0.0–0.0) | 12 | 2.5 (1.0–11.0) | 4 | 1.0 (1.0–2.0) |
Severe | 1 | 2.1 (2.1–2.1) | 0 | - | 1 | 3.0 (3.0–3.0) | 0 | - |
All | 45 | 1.0 (0.0–4.0) | 7 | 0.0 (0.0–14.0) | 45 | 1.0 (1.0–11.0) | 6 | 1.0 (1.0–15.0) |
Nausea |
Mild | 8 | 1.8 (0.0–4.0) | 1 | 3.0 (3.0–3.0) | 8 | 2.5 (1.0–4.0) | 1 | 24.0 (24.0–24.0) |
Moderate | 3 | 0.0 (0.0–3.0) | 1 | 2.0 (2.0–2.0) | 3 | 2.0 (1.0–4.0) | 1 | 8.0 (8.0–8.0) |
Severe | 0 | - | 0 | - | 0 | - | 0 | - |
All | 11 | 1.6 (0.0–4.0) | 2 | 2.5 (2.0–3.0) | 11 | 2.0 (1.0–4.0) | 2 | 16.0 (8.0–24.0) |
Vomiting |
Mild | 1 | 2.0 (2.0–2.0) | 0 | - | 1 | 1.0 (1.0–1.0) | 0 | - |
Moderate | 2 | 1.5 (0.0–3.0) | 0 | - | 2 | 2.0 (2.0–2.0) | 0 | - |
Severe | 0 | - | 0 | - | 0 | - | 0 | - |
All | 3 | 2.0 (0.0–3.0) | 0 | - | 3 | 2.0 (1.0–2.0) | 0 | - |
Fever |
Mild | 14 | 1.2 (0.0–3.0) | 3 | 0.0 (0.0–1.4) | 14 | 2.0 (1.0–3.0) | 3 | 2.0 (1.0–5.0) |
Moderate | 1 | 3.0 (3.0–3.0) | 0 | - | 1 | 3.0 (3.0–3.0) | 0 | - |
Severe | 0 | - | 0 | - | 0 | - | 0 | - |
All | 15 | 1.3 (0.0–3.0) | 3 | 0.0 (0.0–1.4) | 15 | 2.0 (1.0–3.0) | 3 | 2.0 (1.0–5.0) |
The incidence of serious TEAEs regardless of relationship to the study drug was similar in the two treatment groups during the first period: 3 patients (5.8%) on IVIg experienced 5 serious TEAEs, and 2 patients (4.2%) on placebo experienced 4 serious TEAEs. In the overall period, 7 patients (7.4%) experienced a total of 9 serious TEAEs that were considered related to study drug, as shown in Table
4. Following these related serious TEAEs, 2/7 patients (28.6%) were able to resume treatment with IVIg (loss of consciousness in one case and hypoesthesia [TEE] in another). In another case (cerebral infarction [TEE]), the serious TEAE occurred 12 days after the last infusion of IVIg (Table
4). The median (range) latency time for serious related TEAEs where the last infusion was IVIg was 1.95 days (0.0–29.0), and the median duration of the serious related TEAEs was 14.0 days (1.0–109.0).
Table 4
Serious TEAEs assessed as at least possibly related to study druga (overall period)
First period IVIg | Patient 1 | Muscle spasms | Severe | Life threatening | Probable | 1 | Recovered/resolved | Study drug withdrawn |
Dyspnoea | Severe | Life threatening | Probable | 1 | Recovered/resolved |
Extension period (all IVIg) | Patient 2 | Deep vein thrombosis (TEE) | Severe | Hospitalisation and life threatening | Probable | 73 | Recovered/resolved | Study drug withdrawn |
Pulmonary embolism (TEE) | Severe | Hospitalisation and life threatening | Probable | 73 | Recovered/resolved |
Patient 3 | Cerebrovascular accident (TEE) | Moderate | Hospitalisation and medically important | Possible | 109 | Recovered/resolved with sequelae | Study drug withdrawn |
Patient 4 | Pulmonary embolism (TEE) | Moderate | Hospitalisation and medically important | Possible | 14 | Recovered/resolved with sequelae | Study drug withdrawn |
Patient 5 | Loss of consciousness | Moderate | Hospitalisation | Probable | 1 | Recovered/resolved | Dose of study drug unchanged The patient subsequently received a further five cycles of IVIg treatment and did not experience any further serious TEAEs |
Patient 6 | Cerebral infarction (TEE) | Moderate | Hospitalisation and medically important | Possible | 99 | Recovered/resolved with sequelae | The serious TEAE occurred 12 days after the last infusion cycle of IVIg |
Extension period (all IVIg) | Patient 7 | Hypoesthesia (TEE) | Mild | Medically important | Possible | 1 | Recovered/resolved | Dose of study drug unchanged The patient subsequently received one further cycle of IVIg treatment |
Serious TEAEs assessed as unlikely related or not related to study drug included sepsis (n = 1), PE (n = 1), ventricular extrasystoles (n = 1), tropical spastic paraparesis (n = 1), sinus tachycardia (n = 1; 2 events) and hypertension (n = 1) in the first period and squamous cell carcinoma (n = 1), condition aggravated (n = 2), atypical pneumonia (n = 1), pneumonia (n = 1), cardiac failure congestive (n = 1), sepsis (n = 1), acute respiratory failure (n = 1), acute kidney injury (n = 1) and Escherichia bacteraemia (n = 1) in the extension period.
Adverse events of special interest
During the overall period, 8 TEEs were documented in 6 patients treated with IVIg (
n = 664 infusion cycles), and none was reported in patients treated with placebo (
n = 184 infusion cycles). Of the TEEs, six in five patients were assessed as possibly or probably related to the study drug. The median (range) time to TEE occurrence from the start of the first IVIg infusion was 167 days (142–267) and from the last IVIg infusion prior to the event was 12 days (2–29). Overall, most patients had a Wells score of 0 at their last visit prior to the event, including all patients who experienced TEEs. Characteristics of patients with TEEs and details of their TEE risk factors are presented in Table
5. Four of the five patients who experienced possibly or probably related TEEs had hypertension prior to the study. Other risk factors for TEEs included dyslipidaemia and obesity (both
n = 2) and hypercholesterolaemia, chronic heart failure, ex-smoker, palpitations, myocardial ischaemia, ventricular dilatation and left atrial dilatation, supraventricular arrhythmia and osteoporosis and fractures of the spine (all
n = 1). In total, the 89 patients who did not experience TEEs exhibited a total of 51 risk factors from the above-mentioned categories (i.e. an average of 0.6 per patient), versus 16 risk factors among 6 patients who did experience TEEs (i.e. an average of 2.7 per patient), equating to a 4.6-fold difference in the number of risk factors. Compared to patients who did not experience TEEs, patients who experienced TEEs had a higher median age (69.0 versus 51.6 years, respectively) and a numerically higher percentage of occurrence for each of the risk factors analysed, ranging from 2.4- to 15.2-fold higher (Table
6). The six patients with TEEs together experienced a total of 24 related TEAEs (mean, 4 per patient), which was similar to the mean number for all patients (3 per patient). Risk of TEE was highest in patients with three or more risk factors. Global disease activity, disease duration and dosing were similar between groups. The occurrence of these TEEs led to a study protocol amendment, whereby the maximum permitted infusion rate was reduced from 0.12 to 0.04 mL/kg/min. This resulted in a reduction in the incidence of TEEs from 1.54 (95%
CI: 0.42, 3.94) per 100 patient months to 0.54 (95%
CI: 0.07, 1.95) following implementation.
Table 5
Characteristics of patients with TEEs that were deemed possibly or probably related to study drug
Patient 2 | DVT; severe | 67 years Male White race 26.0 kg/m2 | 180 g; 1.978 g/kg 0.12 mL/kg/min Two infusion episodes infused over 340 min | 2 | Moderate | • Hypertension • Chronic heart failure • Dyslipidaemia • Ex-smoker |
PE; severe | 2 |
Patient 3 | Cerebrovascular accident (TEE) | 79 years Female White race 28.0 kg/m2 | 160 g; 2.025 g/kg 0.08 mL/kg/min Four infusion episodes; infused over 555 min | 29 | Moderate | • Hypertension • Palpitations • Myocardial ischaemia • Dyslipidaemia |
Patient 4 | PE; moderate | 62 years Male White race 28.7 kg/m2 | 180 g; 1.978 g/kg 0.04 mL/kg/mina Two infusion episodes infused over 590 min | 24 | Moderate | • Hypertension • Ventricular dilatation and left atrial dilatation • Obesity |
Patient 6 | Cerebral infarction; moderate | 70 years Female White race 22.5 kg/m2 | 110 g; 2.000 g/kg 0.12 mL/kg/min Three infusion episodes infused over 321 min | 14 | Mild | • Hypertension |
Patient 7 | Hypoaesthesia; mild | 67 years Female White race 35.3 kg/m2 | 170 g; 2.000 g/kg 0.04 mL/kg/min Two infusion episodes infused over 592 min | 10 | Severe | • Supraventricular arrhythmia • Hypercholesterolaemia • Osteoporosis of the lumbar spine and fractures of the thoracic and lumbar spine • Obesity |
Table 6
Risk factors for TEEs in patients who did not present with TEEs versus those who presented with TEEs (overall period)
Age, mean (range), years | 51.6 (22–77) | 69.0 (62–79) |
Gender, n (%) female | 68 (76.4) | 3 (50) |
Race, n (%) |
Asian | 2 (2.2) | 0 (0) |
Black or African American | 5 (5.6) | 0 (0) |
White | 81 (91.0) | 6 (100) |
Other | 1 (1.1) | 0 (0) |
TEE risk factors |
Hypertension, n (%) | 31 (34.8) | 5 (83.3) |
Chronic heart failure, n (%) | 1 (1.1) | 1 (16.7) |
Myocardial ischaemia, n (%) | 2 (2.2) | 1 (16.7) |
Dyslipidaemia, n (%) | 4 (4.5) | 2 (33.3) |
Dilation ventricular and left atrial dilation, n (%) | 1 (1.1) | 1 (16.7) |
Obesity, n (%) | 3 (3.4) | 2 (33.3) |
Supraventricular arrhythmia, n (%) | 0 (0.0) | 1 (16.7) |
Hypercholesterolaemia, n (%) | 8 (9.0) | 2 (33.3) |
Osteoporotic fracture, n (%) | 1 (1.1) | 1 (16.7) |
No. of TEE risk factors per patient |
0 risk factors | 50 (56.2) | 0 (0) |
1 risk factor | 28 (31.5) | 1 (16.7) |
2 risk factors | 10 (11.2) | 0 (0) |
3 risk factors | 1 (1.1) | 5 (83.3) |
Physician global disease activity (actual), n (%) |
Mild | 24 (27.0) | 2 (33.3) |
Moderate | 52 (58.4) | 4 (66.7) |
Severe | 13 (14.6) | 0 (0.0) |
Maximum infusion rate per patient, median (range), mL/kg/min |
Pre-introduction of lower infusion rate | 0.12 (0.04–0.12) | 0.12 (0.04–0.12) |
Following introduction of lower infusion rate | 0.04 (0.02–0.08) | 0.04 (0.02–0.08) |
Actual IVIg dose, median (range), g/kg | 1.99 (0.24–2.03) | 1.99 (1.98–2.03) |
No patient experienced a haemolytic transfusion reaction during the study.
Effect of dose reduction
Of 91 patients who entered the extension period, 8 patients (8.8%) had their IVIg dose reduced from 2.0 to 1.0 g/kg at 28 weeks or thereafter, undergoing a total of 23 infusion cycles at the reduced dose. Two of these patients never experienced any related TEAEs under IVIg treatment. Four patients experienced mild related and expected TEAEs under 2 g/kg dosing but none when treated with reduced dose. One patient experienced several related TEAEs of different severity under placebo, as well as severe headache occurring twice under 2 g/kg IVIg dosing, but only one possibly related TEAE (elevated blood pressure of moderate severity) when treated with 1 g/kg IVIg. Another patient experienced several mild and moderate expected TEAEs under 2 g/kg IVIg but only once a mild headache during the reduced IVIg period. At the lower dose, no TEEs occurred, and there were no TEAEs leading to discontinuation of the study drug.
Premedication
Premedication for infusions was given to 10 patients (21.3%) in the IVIg group and 4 patients (8.3%) in the placebo group. In the overall period, premedication was needed by 12 patients (12.6%) receiving IVIg. The most common types of premedication were analgesics and systemic antihistamines, each given to 6.3% of patients. Glucocorticoids were not permitted as premedication. Baseline characteristics of patients on IVIg who received premedication and those who did not were similar, suggesting that none of these factors was associated with requirement for premedication.
Outcomes
In the first period, 3 patients (5.8%) who had received IVIg experienced 8 TEAEs leading to discontinuation of the study drug. Six of these events occurred in a single patient and were considered to be related to study drug (Table
7). The other two events (sepsis and basilar artery stenosis) were reported in one patient each and were considered to be unrelated to study drug.
Table 7
Possibly and probably related adverse events leading to discontinuation of study drug (overall period)
First period IVIg | Patient 1 | Muscle spasms | Severe | Yes | Probable | Recovered/resolved |
Sinus tachycardia | Moderate | No | Probable | Recovered/resolved |
Chills | Mild | No | Probable | Recovered/resolved |
Fever | Mild | No | Probable | Recovered/resolved |
Dyspnoea | Severe | Yes | Probable | Recovered/resolved |
Back pain | Moderate | No | Probable | Recovered/resolved |
Extension period (all IVIg) | Patient 2 | Deep vein thrombosis (TEE) | Severe | Yes | Probable | Recovered/resolved |
Pulmonary embolism (TEE) | Severe | Yes | Probable | Recovered/resolved |
Patient 3 | Vertigo | Moderate | No | Possible | Recovered/resolved |
Vision blurred | Mild | No | Possible | Recovered/resolved |
Cerebrovascular accident (TEE) | Moderate | Yes | Possible | Recovered/resolved with sequelae |
Patient 4 | Pulmonary embolism (TEE) | Moderate | Yes | Possible | Recovered/resolved with sequelae |
Patient 8 | Musculoskeletal pain | Mild | No | Possible | Recovered/resolved |
Paraesthesia | Mild | No | Possible | Recovered/resolved |
Dizziness | Mild | No | Possible | Recovered/resolved |
Condition aggravateda | Mild | No | Not related | Recovered/resolved |
Patient 9 | Headache | Moderate | No | Probable | Recovered/resolved |
Nausea | Moderate | No | Probable | Recovered/resolved |
Patient 10 | Hypersensitivity | Mild | No | Probable | Recovered/resolved |
Patient 11 | Vomiting | Mild | No | Probable | Recovered/resolved |
In the extension period, 10 patients (10.5%) who received IVIg experienced a total of 17 TEAEs leading to discontinuation of the study drug. The most common events leading to discontinuation were ‘condition aggravated’ (preferred term), which led to withdrawal of 3 patients (3.2%; 2 not related, 1 unlikely related), and PE, which led to withdrawal of 2 patients (2.1%; 1 possibly related and 1 probably related). In total, non-related TEAEs leading to discontinuation included three events of condition aggravated and one event of
Escherichia bacteraemia. Related TEAEs leading to discontinuation are presented in Table
7.
No deaths were reported during the study.
Discussion
Dermatomyositis is a subtype of a group of rare systemic autoimmune diseases called idiopathic inflammatory myopathy (IIM), for which there is no cure. Treatment focuses on suppressing or modulating the autoimmune response to restore muscle performance, skin, lung and other organ involvement. IVIg formulations have previously been used off-label for dermatomyositis treatment in combination with immunosuppressive therapies. Primary results from the ProDERM study have been reported separately [
12] showing that IVIg is efficacious and generally safe in patients with dermatomyositis. The additional data presented herein provides evidence that IVIg treatment has a favourable safety and tolerability profile in the treatment of patients with dermatomyositis.
Of 95 patients receiving IVIg in the ProDERM study, only 8 discontinued therapy due to drug-related TEAEs. Most TEAEs were reported during or within 72 h of receiving an infusion and were mild and short lasting, with similar latency times and duration between treatment groups. There were no haemolytic transfusion reactions or deaths reported. Most patients in the study received a combination of immunosuppressive drugs and IVIg.
Previously reported safety data of IVIg treatment in dermatomyositis is limited. One randomised controlled trial, a 3-month crossover trial comparing IVIg and prednisone to placebo and prednisone in 15 refractory adult patients, reported better efficacy with IVIg as compared to placebo [
22]. As in the ProDERM study, patients tolerated IVIg infusions well; however, two patients experienced severe headache with each infusion, necessitating treatment with narcotics [
22]. Nevertheless, these patients still experienced a major improvement in their condition following IVIg treatment and stated that the benefit far outweighed the adverse effect [
22].
In juvenile dermatomyositis, a 4-year review of nine children also reported that headaches were common after treatment with IVIg, especially after the initial treatment [
23]. Headaches were mostly mild, but four of the nine children also experienced severe episodes. Two patients experienced diarrhoea, one severe nausea and one fever [
23]. The authors noted considerable variability of side effects, and that lengthening the infusion to 5 days rather than 3 prevented IVIg-related side effects [
23]. In a non-randomised study of IVIg in 20 adults with refractory polymyositis or dermatomyositis in combination with prednisone and cyclosporin A, overall safety results noted only minor adverse events including gastrointestinal intolerance (nausea or vomiting) [
24]. A recent open-label trial of IVIg in newly diagnosed IIM patients (including nine dermatomyositis patients) also reported mild and transient flu-like symptoms, with no adverse events leading to study withdrawal [
25]. Similar mild to moderate adverse reactions were also reported in another randomised study from Japan [
26].
The aforementioned side effects from IVIg are similar to those observed in other diseases, where more than 80% of IVIg-associated side effects are mild and occur during or shortly after infusion [
27]. A retrospective study of IVIg patients with neuromuscular disease found a similar pattern of AEs, including headache, nausea and fever; although the rates cannot be compared fairly as the patients, dosing regimens and study design differed between this and our analysis [
28]. However, taken together, other published studies confirm that most of the observed TEAEs in the ProDERM study are consistent with the known safety profile of IVIg therapy.
More serious adverse reactions associated with IVIg administration include TEEs, with arterial TEEs being the most common [
27]. In 2013, the US Food and Drug Administration (FDA) mandated that IVIg products include a black box warning regarding the risk of TEEs, which have been reported in 0.5–15% of patients treated with IVIg [
29]. In a 10-year retrospective study assessing IVIg-related adverse events in different diseases, tolerability varied significantly between individuals and IVIg preparation [
30]. For the preparation of IVIg used in this study specifically, the rate of TEEs in a study including all indications was 3 in 21,780 infusions, of which 1 was deemed possibly related to IVIg [
31]. In a study of patients with neurological disorders, the rate of TEEs was 1 in 3374 infusions [
32], and in patients with immune thrombocytopenia, there were no cases of TEE with 626 infusions [
33]. In a recent cohort study of 458 patients with a definitive diagnosis of dermatomyositis, six of 178 patients (3.4%) who received IVIg in the preceding 4 weeks experienced venous thromboembolism (VTE) versus 16 of 280 patients who had not received IVIg. No significant difference was found between groups, suggesting that IVIg was not associated with an increase in VTE risk in these patients [
34]. In the ProDERM study, patients with known history of TEE were excluded; however, results from the overall analysis showed that patients with certain risk factors for TEEs were more likely to experience TEEs than those without. Similarly, a study of data from the UK Biobank from 502,492 individuals on IVIg found that the rate of TEEs was threefold higher in patients with a history of TEE than those without [
35].
Systemic inflammation associated with dermatomyositis may also increase the risk of TEEs. Systemic inflammation is postulated to modulate thrombotic responses by upregulating procoagulants, downregulating anticoagulants and suppressing fibrinolysis [
36]. Indeed, there are several reports of a higher risk of TEEs in patients with dermatomyositis compared to the general population [
37‐
39]. These reports included different variables, such as duration of disease, age and sex, although none looked specifically at treatment (including IVIg). For example, a Swedish study that used nationwide registers found 26.8 (95% confidence interval: 0.9, 52.6) venous thromboembolic events occurred in every 1,000 person-years in dermatomyositis patients (
n = 154) versus 2.4 (0.9, 3.8) in the general population (
n = 4,459), with a hazard ratio of 16.44 [
40]. Hence, TEE monitoring in patients treated with long-term, high-dose IVIg for dermatomyositis is recommended throughout the duration of IVIg treatment as latency of TEEs is highly variable in different patients. In this study, patients who experienced TEEs had a Wells score of 0 at their last visit prior to the event. Therefore, additional risk assessments might help to prevent TEEs.
One possible way to reduce the rate of side effects is to reduce the rate of infusion [
27], and this was supported by results from this analysis showing that reducing the infusion rate from 0.12 to 0.04 mL/kg/min was important in mitigating TEEs. TEE complications can also be prevented through greater vigilance in high-risk subjects, as well as the judicious use of anticoagulation therapy [
27].
Besides reducing the rate of IVIg infusion, the rate of other IVIg-related TEAEs can be reduced by co-administering or pre-medicating with paracetamol, antihistamines or glucocorticoids [
27,
30]. In the current study, routine prophylactic premedication was not permitted and premedication was only required for a small number of patients who had experienced two consecutive infusion-related AEs; analgesics and systemic antihistamines were most commonly administered.
Limitations of the trial include a short follow-up time of less than a year, which did not permit the capture of longer-term safety data. Also, specific subsets of dermatomyositis, including juvenile dermatomyositis, cancer-associated and amyopathic dermatomyositis, were excluded from the study, preventing our safety data from being translatable to these subgroups. The TEE risk factors highlighted in this study were identified based on the general medical history of the subjects and were not formally weighted. In addition, smoking status, a classic risk factor for TEE, was not assessed in the study.
Declarations
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki, in compliance with good clinical practice guidelines. Informed consent was obtained from each patient before any study-related procedures were conducted.
The study was approved by the following ethics committees: Ethik-Kommission des Landes, Berlin, Germany; Bioethics Committee at the National Institute of Geriatrics, Rheumatology and Rehabilitation in Warsaw, Poland; Medical Research Council, Ethics Committee for Clinical Pharmacology (ECCP), Budapest, Hungary; Ethics Committee for Multi-Centric Clinical Trials, The University Hospital Kralovske Vinohrady, Prague, Czech Republic; Ministry of Health of the Russian Federation (MOH) Council of Ethics, Moscow, Russia; Amsterdam UMC, Medical Review Committee AMC, Amsterdam, Netherlands; National Bioethics Committee for Medicines and Medical Devices, Bucharest, Romania; Ethics Committee at Sumy Regional Clinical Hospital, Public Institution of Sumy Regional Council 18, Ukraine; Ethics Committee Ternopil University Hospital, Ternopil, Ukraine; Ethics Committee at the Ivano-Frankivsk City, Clinical Hospital No. 1, Ivano-Frankivsk, Ukraine; Jewish General Hospital - Research Ethics Committee, Quebec, Canada; Western Institutional Review Board, Puyallup, WA, USA; IntegReview, Austin, TX, USA; UCLA IRB, Institutional Review Board, University of California LA, USA; The University of Kansas Medical Center Institutional Review Board, KS, USA; University of Michigan Medical School Institutional Review Board; Mayo Clinic Institutional Review Board, Rochester, MN, USA; Oregon Health & Science University Independent Review Board, Portland, OR, USA; and UMiami Human Subject Research Office (M809), Miami, FL, USA.
Competing interests
RA has received grants or contracts from Mallinckrodt, Pfizer, Bristol Myers-Squibb, Boehringer Ingelheim, Q32, EMD Serono and Janssen; and consulting fees from Mallinckrodt, Octapharma, CSL Behring, Bristol Myers-Squibb, Alexion, Boehringer Ingelheim, Janssen, Roivant, Galapagos, Abbvie, Horizontal Therapeutics, Biogen, ANI Pharmaceutical, Capella, Ililli, Medicxi, EMD Serono, Kezar, Pfizer, Astra Zeneca, Argenx, Corbus, Kyverna, Merck, Actigraph, Scipher, Teva, Beigene, Nuvig, Cabaletta Bio and Sanofi. JS has received support for the current manuscript and funding and consultancy fees from Octapharma; and honoraria for presentations, from Pfizer. CC-S has received grants or contracts from Pfizer, Bristol Myers Squibb, Abbvie, CSL Behring, Alexion and Priovant; consulting fees from Pfizer, Bristol Myers Squibb, Abbvie, Octapharma, Priovant, Galapagos, Recludix and Boehringer Ingelheim Pharmaceuticals; and participated on a Data Safety Monitoring Board or Advisory Board for Bristol Myers Squibb. ZB-C has received payment or honoraria for lectures from Sanofi, Berlin-Chemie and Abbvie; support for attending meetings from Sanofi and Biotest AG; and unpaid board membership in the Hungarian Dermatology and Immunology and Allergy Societies. MMD has received grants or contracts from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, UCB Biopharma/RaPharma, Viromed/Healixmith and TMA; consultancy fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and participated on a Data Safety Monitoring Board or Advisory Board for Abcuro, Amazentis, ArgenX, Astellas, Catalyst, Cello, Covance/Labcorp, CSL-Behring, EcoR1, Janssen, Kezar, MDA, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, Roivant Sciences Inc, Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, Abata/Third Rock and UCB Biopharma; and received royalty fees or licenses, consultancy fees, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from UpToDate. ZG has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Lilly, Novartis, Roche; received support for attending meetings and/or travel from Biotest, CSL Behring, Novartis, Abbvie and Lilly; and participated on a Data Safety Monitoring Board or Advisory Board for Octapharma. CVO has received research support from Genentech and consulting fees from Pfizer. JV has received support for the current manuscript from the Czech Ministry of Health; grants or contracts from Abbvie; consulting fees from Argenx; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Werfen and Octapharma; and Participated on a Data Safety Monitoring Board or Advisory Board for Horizon, Kezar, Boehringer and Octapharma. IB was an employee of Octapharma Pharmazeutika Produktionsges.m.b.H until June 2022; and has subsequently received Consulting fees from Octapharma. EC is an employee of Octapharma Pharmazeutika Produktionsges.m.b.H. TL is a consultant for FFF Enterprises. SM and ES have no conflicts of interest to declare.
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