Immunomodulation with intravenous immunoglobulins (IVIG)
IVIG consist of pooled polyclonal immunoglobulins derived from healthy donors. The precise mechanism by which IVIG suppress autoimmune inflammation has not been established definitively, but is likely to involve a plethora of molecular effects via their Fab- or Fc-fragments :
Preparation and administration: for induction therapy of neurological autoimmune diseases, IVIG are administered intravenously at a dose of 2 g/kg (corresponding to 5 × 0·4 g/kg/day) of body weight once monthly for 3–6 months. Subsequently, maintenance therapy dose range is 0·1–0·4 g/kg of body weight, approximately every 4 weeks (depending on the individual patient's clinical course). IVIG effects usually last between 2 weeks and 3 months.
Clinical trials: in MS, IVIG have been tested for their efficacy in (i) relapse treatment, their impact on the (ii) relapse rate and disease progression in RRMS and on (iii) disease progression in SPMS.
Two studies compared IVIG versus
placebo as add-on treatment to methylprednisolone in acute MS relapse. There was no statistically significant difference between the treatment groups [28, 29]
. Thus, IVIG are currently not recommended for the treatment of acute relapses in MS.
A well-designed trial with 127 patients with RRMS did not show a statistically significant reduction of the relapse rate and disease progression between two IVIG treatments (0·2 g/kg and 0·4 g/kg monthly) and placebo 
. Thus, despite earlier trials suggesting some efficacy of IVIG in RRMS they are currently not recommended as first-line therapy for the disease-modifying treatment of patients with RRMS.
A randomized, placebo-controlled clinical trial (ESIMS) including 318 patients with SPMS compared IVIG (1 g/kg monthly) to placebo and did not show a difference in clinical parameters 
. With regard to MRI outcomes, there was a delayed reduction of brain volume in the IVIG group 
, but the relevance of this finding is not clear. These data do not allow for a recommendation of IVIG in progressive MS and it can be concluded that IVIG is not effective in delaying disease progression in SPMS. Thus, IVIG are currently not recommended for the disease-modifying treatment of patients with SPMS.
In CIDP, several short-term clinical trials showed beneficial effects of IVIG compared with placebo, plasma-exchange or steroids [33-35]. However, long-term data on the efficacy of IVIG in CIDP have emerged only recently.
A recent randomized, double-blind, placebo-controlled, response-conditional cross-over trial included 117 patients with CIDP (ICE trail). The long-term efficacy of IVIG (baseline loading dose of 2 g/kg over 2–4 days and then a maintenance dose of 1 g/kg over 1–2 days every 3 weeks for up to 24 weeks) was compared with placebo . IVIG or placebo was administered for up to 24 weeks in an initial treatment period; patients who did not show an improvement in INCAT disability score of ≥1 point received the alternate treatment in a cross-over treatment period. Patients who showed an improvement and completed 24 weeks of treatment were eligible to be reassigned randomly in a blinded 24-week extension phase.
The primary outcome was the percentage of patients who had maintained an improvement from baseline in adjusted INCAT disability score of 1 point or more to week 24. Secondary efficacy outcomes were (i) mean change from baseline in maximum grip strength at end-point during the initial treatment period; (ii) mean change from baseline in the compound muscle action potential amplitude after stimulation of the most severely affected motor nerve at the proximal site at end-point during the first period; and (iii) time to relapse for patients who were first-period adjusted-INCAT responders or cross-over-period adjusted-INCAT responders to IVIG and entered the extension phase. Relapse during the extension phase was defined as worsening of adjusted INCAT disability score by 1 point or more from the extension baseline value.
During the initial treatment period, 54% of patients treated with IVIG and 21% of patients who received placebo had an improvement in adjusted INCAT disability score that was maintained to week 24 (treatment difference 33·5%; P = 0·0002). Improvements from baseline to end-point were also recorded for grip strength in the dominant hand (treatment difference 10·9 kPa; P = 0·0008) and the non-dominant hand (8·6 kPa; P = 0·005). Results were similar during the second cross-over period. During the extension phase, participants who continued to receive IVIG had a longer time to relapse than did patients treated with placebo (P = 0·011).
This is the first study that demonstrates clearly the long-term efficacy and tolerability of IVIG in CIDP.
Another recent, multi-centre, randomized, double-blind, placebo controlled, parallel-group study in 45 patients with CIDP compared the efficacy and tolerability of IVIG (0·5 g/kg/day for 4 consecutive days) to intravenous methylprednisolone (0·5 g/day for 4 consecutive days) given every month for 6 months . After therapy discontinuation, patients were followed-up for 6 months to assess relapses. The primary outcome was the number of patients discontinuing either therapy owing to inefficacy or intolerance. Secondary end-points included the proportion of patients experiencing adverse events or worsening after therapy discontinuation.
More patients stopped methylprednisolone (52%) than IVIG (13%) (P = 0·0085). The reasons for discontinuation were lack of efficacy, adverse events or voluntary withdrawal. After therapy discontinuation, more patients on IVIG worsened and required further therapy (38%) than did those on methylprednisolone (none) (P = 0·0317). Thus, treatment of CIDP with IVIG for 6 months was discontinued less frequently because of inefficacy, adverse events or intolerance than treatment with intravenous methylprednisolone.
Another recent prospective, multi-centre, single-arm, open-label Phase III study [Privigen® Impact on Mobility and Autonomy (PRIMA) trial] evaluated the efficacy and safety of IVIG in 28 patients with CIDP . Patients received one induction dose of IVIG (2 g/kg body weight) and up to seven maintenance doses (1 g/kg body weight) at 3-week intervals. The overall responder rate defined as an improvement of ≥1 point on the INCAT disability scale at completion was 60·7%. IVIG-pretreated patients demonstrated a higher responder rate than IVIG-naive patients (76·9 versus 46·7%). The INCAT score, the maximum grip strength and the Medical Research Council sum score all improved significantly at completion compared to baseline.
Thus, these recent trials provide evidence for the long-term efficacy of IVIG in patients with CIDP.
Adverse effects, frequent: headache, hypertension, allergic/anaphylactic reactions [especially in immunoglobulin (Ig)A-deficient patients], dermatitis; infrequent: infection (HIV or viral hepatitis) by contaminated blood product, pulmonary oedema from fluid overload, due to the high colloid oncotic pressure of IVIG, venous thrombosis, aseptic meningitis and haemolysis.