Three controlled trials of intravenous immunoglobulin therapy in patients with ME/CFS

A translation to Dutch for this article is available here.

Introduction

Therapy with high-dose intravenous immunoglobulin (IVIG) has been demonstrated to be useful in several diseases, from autoimmunity mediated by autoantibodies (such as Guillain-Barré syndrome, myasthenia gravis, etc.) to primary and secondary antibody deficiency states. It has also been recommended in inflammatory conditions (myopathies) and in some infectious diseases (viral pneumonitis after transplantation, severe or recurrent Clostridium difficile colitis) (UK Guidelines, 2009). This kind of treatment is sometimes offered to ME/CFS patients too, with a wide range of doses, frequency, and number of administrations. In what follows I have searched for trials of IVIG in ME/CFS patients, seeking for evidence of efficacy.

Selected papers

I collected a total of 5 studies on the use of IVIG in ME/CFS patients. One of them (Rowe KS 1997) has been discarded because it is on a pediatric population. Another one (Tirelli U et al. 2013) represents a retrospective evaluation of 741 ME/CFS patients treated with various approaches (IVIG among them), but doses and frequency of interventions are not reported. Moreover, patients treated with IVIG have been clustered with those treated with antivirals, so it is not possible to identify a group of patients to whom IVIG was given without other treatments. For all these reasons this paper has been discarded. The remaining three studies are placebo-controlled trials, conducted on adults (Peterson PK et al. 1990), (Lloyd A et al. 1990), (Vollmer-Conna U et al. 1997). Results from these studies have been collected in Table 1.

Table 1. F/M: female patients/male patients. D/P: patients who received the drug/patients who received placebo.

Results from the three placebo-controlled trials

The first study (Peterson PK et al. 1990) is on the administration of six infusions of IVIG, one month apart at a dose of 1 gram/kg. Patients were evaluated throughout the whole trial and no improvements were reported in those treated with IVIG, versus the placebo group. Patients have been recruited according to Holmes’ criteria (Holmes GP et al. 1988) and most of them presented moderate to severe post-exertional malaise. Only 32% reported moderate to severe confusion (indicated as “brain fog” in Table 1). This trial’s negative result has been confirmed by the third study here discussed (Vollmer-Conna U et al. 1997), where again 1 gram of IVIG for kg, administered once a month, led to no benefit versus placebo. This same study evaluated other doses (0.5g/kg, 2g/kg) and none of them was effective. The only study with a positive outcome is the second one (Lloyd A et al. 1990), where three administrations of 2g/kg each – once a month – determined a significant improvement in 10/23 patients (43%), while only 3/26 (11%) patients treated with placebo experienced a relief.

Discussion

One of the three controlled trials reported a significant response to 2g/kg IVIG a month, versus placebo (Lloyd A et al. 1990). This result has not been confirmed by the subsequent study by the same group of researchers (Vollmer-Conna U et al. 1997). Lower dosages have been unsuccessful (Peterson PK et al. 1990), (Vollmer-Conna U et al. 1997). It is worth noting that in the only positive study, inclusion criteria required “abnormal T cell-mediated immunity indicated by reduction in absolute count of T8 and/or T4 lymphocyte subset, and/or cutaneous anergy” (Lloyd AR et al. 1988) and the Authors reported that low CD4 lymphocyte count at baseline was a predictor for response. This could indicate that a subgroup of ME/CFS patients with an immune deficiency in Th cells could represent a population of responders to IVIG.

Conclusion

These three controlled trials do not seem to support the use of IVIG in ME/CFS, even if there is some data in favor of the use of the highest dosage (2g/kg/month) in patients with low CD4 count.

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