Effects of intravenous immunoglobulin therapy in Japanese patients with polymyositis and dermatomyositis resistant to corticosteroids: a randomized double-blind placebo-controlled trial

Abstract

High-dose intravenous immunoglobulin (IVIG) therapy has been effective in treating various autoimmune and systemic inflammatory diseases. Here, we assessed the efficacy and safety of IVIG therapy with polyethylene glycol-treated human IgG (drug code GB-0998) for patients with corticosteroid-refractory polymyositis (PM) and dermatomyositis (DM) by means of a randomized, double-blind, placebo-controlled study. We randomly assigned 26 subjects (16 PM and 10 DM) to receive either GB-0998 or placebo. Intragroup comparison in the GB-0998 group showed statistically significant improvements due to GB-0998 administration in the primary endpoint (manual muscle test score) and secondary endpoints (serum creatine kinase level and activities of daily living score). However, significant improvements were also found in the placebo group, and comparison of the GB-0998 group with the placebo group did not show any significant difference between the groups. We discuss possible reasons for the absence of a clear intergroup difference in efficacy. Nineteen adverse drug reactions were observed in 11 of 26 subjects (42.3%), of which 2 events (decreased muscle strength and increased serum creatine kinase) were assessed as serious; however, they are previously known events. These results indicate that GB-0998 can be safely used with the same precautions as other current IVIG therapy.

Fig. 1

Outline of study design. GB-0998 (active drug) was administered to the GB-0998 group in the first period and to the placebo group in the second period. Differences between before and after the 8-week first period in the GB-0998 group were assessed in the primary analysis

Fig. 2

Flow diagram of patients participating in this trial. In this study, a total of 26 subjects received GB-0998. Asterisk Premature discontinuation occurred after the sixth week of the first period

Fig. 3

Kaplan–Meier curve of patients for whom the MMT scores increased by 5 points or more in the first period. Event occurrence was defined as the time point when MMT scores initially increased by 5 points or more, and subsequently remained at the higher level, during the period from before drug administration until transfer to the second period. When the score was increased by less than 5 points upon transfer to the second period, the test was discontinued on day 56

Fig. 4

Kaplan–Meier curve of patients in whom serum CK level was normalized in the first period. Event occurrence was defined as the first decline of the serum CK level to below the upper limit of the normal range during the first phase. In one subject whose serum CK level was not normalized on day 57, the test was discontinued on day 58

Fig. 5

Kaplan–Meier curve of patients discharged from hospital in the first period. Event occurrence was defined as the first discharge from hospital after test drug administration in the first period

Fig. 6

a Time-dependent changes in the rate of improved MMT scores in the first period. When MTT score increased by 5 points or more compared with that before administration of the drug, this was defined as an improvement. The time-dependent changes in the rate of improvement are shown by group. For cases discontinued or transferred to the second period before 8 weeks after the start of administration in the first period, the assessment in each assessment period was performed using the LOCF approach. Fisher’s exact test was used to compare the rates of improved MMT scores between the two groups at the end of the first 8-week period. b An MTT score that increased by 5 points or more compared with before drug administration in the first period was considered as an improvement, and improvement rates after 8 weeks in the first period and after 8 weeks in the second period were compared by group. For subjects discontinued or transferred to the second period before the end of the 8-week first period, the assessment after the first period was performed using the LOCF approach. For subjects discontinued before the end of the 8-week second period, the assessment after the second period was performed using the same method

Fig. 7

Forest plots of before–after differences in MMT scores for the 8-week first period. Black circles and lines, respectively, represent point estimates and 95% confidence intervals of between-group differences (GB-0998 group versus placebo group) concerning MMT scores for each assessed muscle

Fig. 8

Forest plots of before–after differences in ADL scores for the 8-week first period. Black circles and lines, respectively, represent point estimates and 95% confidence intervals of between-group differences (GB-0998 group versus placebo group) in the ADL scores for each activity

Fig. 9

Time-courses of MMT scores of individual subjects for 8 weeks after initiation of first-period administration (a GB-0998 group, b placebo group). Broken lines indicate the time-courses after transfer to the second period in the cases of subjects who were transferred before the full 8 weeks in the first period

Fig. 10

Time-courses of serum CK levels of individual subjects for 8 weeks after initiation of first-period administration (a GB-0998 group, b placebo group). Broken lines indicate the time-courses after transfer to the second period in the cases of subjects who were transferred before the full 8 weeks in the first period