Recommendations and supporting considerations (supporting information) (a) IVIg vs placeboThe TF strongly recommended treatment with IVIg. Induction treatment: The usual total IVIg dose is 2 g/kg, divided over 2 to 5 days. Since not all patients respond to this first course, two to five repeated doses of 1 g/kg IVIg every 3 weeks may be required before either the patient improves or it can be decided that IVIg is ineffective. Alternatively, clinical experience indicates that a second course of 2 g/kg a few weeks after the first course may be sufficient to decide whether IVIg is ineffective. Maintenance treatment: Most patients require IVIg maintenance treatment. The best IVIg maintenance dose and schedule are not known. The most commonly used IVIg maintenance regimen in clinical trials is 1 g/kg every 3 weeks, but in clinical practice lower doses and longer treatment intervals maintaining maximal sustained improvement should be considered (eg, 0.4-1 g/kg every 2-6 weeks) Objective end-of-dose deterioration before the next IVIg infusion should be minimised. If it occurs, the IVIg dose may be increased or the infusion interval shortened. If the patient is clinically stable, it is recommended to check periodically whether the IVIg dose can be reduced (eg, by 25% per infusion), the treatment interval lengthened, or the treatment discontinued. Based on clinical experience, this could be done once every 6 to 12 months for the first 2 to 3 years of treatment, then less frequently (eg, every 1-2 years). Evidence summary: According to high certainty evidence (5 trials, 269 participants),104 induction treatment with IVIg produced more short-term improvement than placebo. Adverse events were more common with IVIg than placebo (high certainty evidence), but serious adverse events were not observed (moderate certainty evidence, 3 trials, 315 participants).105 The ICE randomized controlled trial showed that 94% of patients responded to 2 g/kg induction treatment and two subsequent treatments of 1 g/kg at 3 weeks intervals.161 The open PRIMA and PRISM studies indicated that a treatment response sometimes may only be observed after three to five infusions of 1 g/kg every 3 weeks.162, 163 Alternatively, clinical experience indicates that most patients respond objectively to no more than two initial courses of 2 g/kg.164 It is not well known whether an objective response following only after several treatments is due to a delayed treatment response or to the requirement of a different treatment regimen. The 1 g/kg every 3 weeks regimen used in the ICE trial for 6 months is often considered as a standard maintenance treatment,161, 165 although the IMC trial comparing IVIg with corticosteroids used an IVIg maintenance dose of 2 g/kg every 4 weeks.166 Experience from clinical practice indicates that the IVIg maintenance dose can be lower (0.4-1 g/kg every 2-6 weeks), but this should be individually adjusted.164, 167-169 There is no evidence of a difference in efficacy between different IVIg preparations for treating CIDP. A randomized controlled trial in 27 patients with CIDP comparing 5% freeze-dried and 10% liquid IVIg preparations showed no difference in treatment efficacy.170 Clinical experience indicates that a switch to another preparation may be helpful to relieve side-effects.

Rationale: The TF considered that the demonstrated efficacy of IVIg in trials, together with extensive practical experience of effectiveness, outweigh the frequent minor and the rare but more serious side-effects. IVIg treatment is acceptable and feasible. The major barriers are the high cost, the inconvenience for the patients, and the need for venous access. The initial IVIg treatment course is usually given in a hospital or day care facility. Maintenance IVIg infusions usually can be administered at a day care facility, infusion centre, or in some countries at home with proper monitoring. Potential burden of repeated infusions and high health care costs of IVIg may outweigh the benefit from treatment in low disability disease.

(b) IVIg vs corticosteroidsBoth IVIg and oral or IV corticosteroids are first-line treatments for CIDP. Based on the level of evidence, the TF did not recommend an overall preference for either treatment modality and weakly recommended either IVIg or corticosteroid treatment.

Both short- and long-term effectiveness, risks, ease of implementation, and cost should be considered:

IVIg may be preferable when it comes to short-term treatment effectiveness, or when (relative) contraindications for corticosteroids exist. There is some indication that pulsed corticosteroids may be preferable for long-term treatment effectiveness, because of a possible higher rate and longer duration of remission, or when IVIg is unaffordable or unavailable. Evidence summary: There is little or no difference in short-term improvement of disability with IVIg in comparison with oral prednisolone (moderate certainty evidence; 1 trial, 29 participants) or long-term improvement after IV methylprednisolone (high-certainty evidence; 1 trial, 45 participants).105 Clinical improvement after IVIg, however, may be faster and the adherence to the treatment seems to be better after IVIg than after IV methylprednisolone.166 Side-effects of long-term treatment are probably in favour of IVIg (real-life experience). Pulsed IV corticosteroid treatment, however, may increase the rate and duration of remission after 6 months as compared with IVIg based on one small study (low certainty evidence).160 A trial comparing standard oral prednisolone vs pulsed dexamethasone treatment did not show a difference in remission rate.159

Rationale: The reason for selecting either IVIg or corticosteroid treatment is based on a series of patient-oriented considerations. Chronic high-dose oral corticosteroid treatment probably has a higher chance of side-effects compared with IVIg, but data on long-term (>6 months) corticosteroid treatment in CIDP are not available. IVIg is considerably more costly than corticosteroids. Co-morbidity may be important for the choice of treatment. IVIg is preferable when there is an increased risk of developing osteoporosis or diabetes. In children, tablets are better tolerated than regular IV treatments but an effect on growth should be considered.

(c) IVIg vs plasma exchangeAlthough the evidence from studies is limited, the TF weakly recommended treatment with IVIg compared with plasma exchange, mainly based on the ease of administration of IVIg. In some patients with good vascular access, plasma exchange may be an acceptable option for chronic treatment.

Evidence summary: Both treatments are considered effective, although the research evidence based on comparative studies is sparse (very low certainty evidence). For induction treatment, plasma exchange and IVIg seem equally effective.105, 171, 172 Doses used in comparative studies are for IVIg: 0.4 g/kg weekly for 3 weeks, then 0.2 g/kg weekly for the next 3 weeks, and for plasma exchange: 2×/week for 3 weeks, then 1×/week for 3 weeks. For maintenance treatment, no proper studies on long-term efficacy and safety of plasma exchange exist. Long-term treatment effects of IVIg are much better known. Especially in small children, IVIg is preferred over plasma exchange, mainly for practical reasons. Non-controlled studies indicated that plasma exchange can still be effective if treatment with IVIg or corticosteroids fails.106

Rationale: The main advantage of IVIg is the relative ease of administration (although plasma exchange often can be delivered through peripheral vein access if using a centrifugal machine). IVIg infusion does not require special equipment. If plasma exchange can be delivered through a peripheral vein, the side-effect profile is usually good. Both treatments are expensive, but IVIg is usually even more expensive than plasma exchange. The cost of plasma exchange is dependent not only on the costs of the equipment, but also on the costs of replacement fluids such as albumin or fresh frozen plasma. These costs may vary in different countries. In children, IVIg is preferred over plasma exchange, mainly for practical reasons.

(d) SCIgThe TF strongly recommended using SCIg for maintenance treatment in CIDP. The TF recommended no preference for either IVIg or SCIg for maintenance treatment in CIDP. During follow-up, the dose should be tailored according to individual treatment response. The TF weakly recommended against using SCIg for induction treatment in CIDP. Evidence summary: Efficacy of SCIg, compared with placebo, has been demonstrated in two randomized controlled trials with high certainty evidence (PATH trial in 172 patients173) and another randomized controlled trial in 30 patients174 in CIDP patients previously responsive to IVIg. There is insufficient evidence that a higher dose (0.4 g/kg weekly) is superior to a lower dose (0.2 g/kg weekly) for maintenance treatment.95 However, a 24-week open-label extension study indicated that there were lower relapse rates in the higher dose group.175 Therefore, long-term dosing should be individualized and tailored to find the most appropriate dose. There are frequent minor side-effects (mainly skin reactions). Limited available information indicates that patients with CIDP might in some cases require higher mean doses of SCIg compared with their previous IVIg dose. There is only very low certainty evidence for using SCIg as induction treatment (one randomized controlled cross-over trial in 20 patients).175

Rationale: When CIDP patients switch from IVIg to SCIg, it is reasonable to start using the same mean dose (1:1) per week. If the treatment effect is insufficient, the dose should be adjusted using reliable outcome measures. If the dose is high (>20-30 g/infusion), an option is to split doses, increase frequency or to use multiple injection sites for subcutaneous infusions. Patients' personal preferences should be considered in choosing SCIg or IVIg. Arguments favouring SCIg include the autonomy and convenience of self-treatment at home, avoiding intravenous cannulation, and possibly fewer systemic side-effects. Disadvantages of SCIg include local side-effects (subcutaneous swelling and pain) and more frequent infusions. Maintenance treatment with SCIg is acceptable and usually feasible.