Peripheral neuropathies: current evidence for alternative treatment regimens and treatment combinations

Evidence-based data for the treatment of immune-mediated neuropathies with drugs other than intravenous immunoglobulins (IVIg) are scarce. Standard treatments, such as corticosteroids and plasmapheresis, are not always effective in these diseases. An overview of current clinical practice, existing data and ongoing research into alternatives to immunoglobulin (Ig) therapy for patients with refractory Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) will be explored here.

GBS

In patients with GBS, Ig and plasmapheresis are the only known effective treatments, with approximately equal efficacy rates. A trial in 383 patients, investigating whether treatment using a combination of IVIg and plasmapheresis conveyed additional benefit, showed that the combination brought no benefit over either treatment alone 1.

It was also considered that a combination of corticosteroids and IVIg might be effective, despite considerable evidence showing that corticosteroids alone are not beneficial 2. A study was conducted involving 225 GBS patients who were unable to walk 3, but neither the patients’ walking nor their disease scores were improved with combination therapy (IVIg and methylprednisolone) compared to only IVIg treatment.

As a further alternative combination therapy, immunosuppressants (mycophenolate mofetil) have been investigated in combination with IVIg and corticosteroids. Data show that this combination conferred no significant benefit over IVIg and methylprednisolone in combination 4.

Multifocal motor neuropathy

In MMN patients, it has been shown that treatment with corticosteroids or plasmapheresis is not an effective therapy, and these treatments can actually worsen the pareses 5.

Combination therapies have been trialled, but to no significant effect. One randomized controlled trial (RCT) (n = 28) investigated the use of an immunosuppressant, mycophenolate mofetil, in combination with IVIg, the only treatment with proven efficacy in this disease. The primary end-point was a 50% reduction in mean weekly IVIg dose 6. After 12 months of treatment, there was no significant difference in IVIg reduction compared to placebo, with only one active patient achieving the primary end-point. In another, open-label trial (n = 6) 7, rituximab was investigated in conjunction with IVIg in an attempt to reduce IVIg requirement. After 12 months, this combination therapy did not reduce the patient's IVIg requirement, nor did it improve patient symptoms.

Cyclophosphamide is sometimes used in clinical practice, and there are case-series which point to its efficacy, especially in combination with autologous stem cell transplantation 5. It is recommended in some guidelines for patients who are refractory to IVIg or who deteriorate; however, it is recommended to give it carefully and with caution, as there is a high rate of serious side effects associated with its use 5.

Chronic inflammatory demyelinating polyneuropathy

There are three treatments with proven efficacy for CIDP patients: IVIg 8, corticosteroids 9 and plasmapheresis 10. Treatment with corticosteroids results in a similar improvement after 6 weeks to that experienced with IVIg 11, with pulsed steroids conferring additional benefit in relation to reducing side effects and achieving remission than lower-dose, continuous steroids 12. A comparison of methylprednisolone with IVIg in an RCT (n = 45) 13 highlighted that subjects treated with IVIg discontinued treatment less frequently due to lack of efficacy (eight subjects in the methylprednisolone group versus three in the IVIg group); however, those patients who did respond to methylprednisolone remained in remission for longer periods of time.

Plasmapheresis has demonstrated treatment efficacy in two small trials 10. Patients experienced an improvement in their symptoms; however, when treatment was stopped they rapidly deteriorated. As yet, there have been no long-term trials looking at repeated plasmapheresis.

The outcome after 6 weeks of treatment is roughly the same between all three of the first-line therapies for CIDP 14. Reviews and retrospective studies have reported the rate of response to these treatments at between 60 and 70% of patients 10,15, while a study of IVIg alone 16 achieved a response rate of 82%. However, there remains a considerable proportion of non-responders for whom alternative therapy options are needed.

A number of combination drug treatments have been trialled in CIDP patients in an attempt to find a therapy for non-responders. An RCT investigating the use of methotrexate in 60 CIDP patients who were already receiving IVIg or corticosteroid treatment aimed to investigate whether the amount of primary treatment administered could be reduced if used in conjunction with methotrexate 17. The results showed no significant difference between methotrexate and placebo. Interim results revealed that patients receiving methotrexate had a higher Medical Research Council (MRC) sum score; however, this was no longer evident at trial completion.

Immunomodulatory drugs have had similarly disappointing results; a review by Cocito et al. 18 analysed data from 110 patients with refractory CIDP who were given immunosuppressants/immunomodulators, mainly in combination with other treatments, and found that the percentage response rates to these were low (17–38%) 18.

Despite this lack of data, drug combinations for the treatment of CIDP are still used in clinical practice; the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines recommend that if all three first-line treatments fail, combination treatments or the addition of immunomodulatory drugs should be considered 19.

There are alternative treatments on the horizon for difficult-to-treat CIDP; therapies currently under investigation include fingolimod, which blocks the migration of white blood cells; alemtuzumab, a leukaemia drug which works by depleting white blood cells; and autologous stem cell transplantation, which has been used already in some case series of difficult-to-treat patients.

In conclusion, although treatment combinations are used in clinical practice in some patients with refractory immune neuropathies, there is not enough evidence to recommend any specific therapy combination or clinical pathway beyond the monotherapies that have proved efficacious in RCTs. More research into alternative treatment options is therefore required.

Disclosures

C. S. has received honoraria for educational talks from Baxter, CSL Behring, Genzyme, and Pfizer. She has received research support from Genzyme.