Review question
We reviewed the evidence for giving people with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) treatment that regulates the immune system other than corticosteroids, immunoglobulin and plasma exchange.
Background
CIDP is an uncommon disease that causes weakness and numbness of the arms and legs. The condition may progress steadily or have periods of worsening and improvement. The cause is inflammation that damages the insulating layer (myelin) around individual nerve fibres. In severe cases, the disease affects the actual nerve fibres themselves. According to Cochrane systematic reviews, three immune system treatments are known to help. These are corticosteroids ('steroids'), plasma exchange (which removes and replaces blood plasma), and intravenous immunoglobulin (infusions into a vein of human antibodies). However, benefit from these is often inadequate or does not last long. We wanted to discover whether other drugs that suppress or change the activity of the immune system are of benefit.
Study characteristics
We found four trials. A trial with 27 participants compared the effects of azathioprine together with steroids to steroids alone for nine months. Azathioprine is a drug that is often used to treat autoimmune diseases because it suppresses the harmful immune cells. This trial had a parallel-group design, which means that the participants were divided into groups that each received only one of the treatments.
A cross-over design trial with 10 participants compared the immune-regulating drug interferon (IFN) beta-1a with placebo (dummy treatment) for 12 weeks. The cross-over design means that all participants received both treatments in random order. A parallel-group trial with 67 participants also compared interferon beta-1a with placebo, but for 32 weeks. Another parallel-group trial with 60 participants compared the cytotoxic drug methotrexate with placebo for 40 weeks. The IFN beta-1a trials, but not the azathioprine or methotrexate trials, received pharmaceutical company support or sponsorship.
Key results
None of these trials showed significant benefit or harm from the drugs. We selected disability scores as our primary measure of the effect of treatment. All the trials were too small to detect or rule out anything but major benefit or harm. We rated the quality of the evidence as moderate or low for IFN beta-1a and methotrexate because of problems with trial design, and because the small number of participants made the result imprecise. We rated the quality of the evidence for azathioprine as low because of lack of blinding and imprecision. Observational studies of these and other drugs, including the cytotoxic drugs cyclophosphamide, ciclosporin, mycophenolate, rituximab, alemtuzumab and natalizumab, peripheral blood stem cell transplantation, and the immune regulating drug interferon (IFN) alfa, exist but are of insufficient quality to determine whether any of these treatments are beneficial.
The evidence is up to date to May 2016.
Low-quality evidence from randomised trials does not show significant benefit from azathioprine or interferon beta-1a and moderate-quality evidence from one randomised trial does not show significant benefit from a relatively low dose of methotrexate for the treatment of CIDP. None of the trials was large enough to rule out small or moderate benefit. The evidence from observational studies is insufficient to avoid the need for randomised controlled trials to discover whether these drugs are beneficial. Future trials should have improved designs, more sensitive outcome measures relevant to people with CIDP, and longer treatment durations.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disease that causes progressive or relapsing and remitting weakness and numbness. It is probably caused by an autoimmune process. Immunosuppressive or immunomodulatory drugs would be expected to be beneficial. This review was first published in 2003 and has been updated most recently in 2016.
To assess the effects of immunomodulatory and immunosuppressive agents other than corticosteroids, immunoglobulin, and plasma exchange in CIDP.
On 24 May 2016, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 4) in the Cochrane Library, MEDLINE, Embase, CINAHL, and LILACS for completed trials, and clinical trial registers for ongoing trials. We contacted the authors of the trials identified and other disease experts seeking other published and unpublished trials.
We sought randomised and quasi-randomised trials of all immunosuppressive agents, such as azathioprine, cyclophosphamide, methotrexate, ciclosporin, mycophenolate mofetil, and rituximab, and all immunomodulatory agents, such as interferon (IFN) alfa and IFN beta, in participants fulfilling standard diagnostic criteria for CIDP. We included all comparisons of these agents with placebo, another treatment, or no treatment.
We used standard methodological procedures expected by Cochrane. We wanted to measure the change in disability after one year as our primary outcome. Our secondary outcomes were change in disability after four or more weeks (from randomisation); change in impairment after at least one year; change in maximum motor nerve conduction velocity and compound muscle action potential amplitude after one year; and for participants who were receiving corticosteroids or intravenous immunoglobulin (IVIg), the amount of this medication given during at least one year after randomisation. Participants with one or more serious adverse events during the first year was also a secondary outcome.
Four trials fulfilled the selection criteria: one of azathioprine (27 participants), two of IFN beta-1a (77 participants in total) and one of methotrexate (60 participants). The risk of bias was considered low in the trials of IFN beta-1a and methotrexate but high in the trial of azathioprine. None of the trials showed significant benefit in any of the outcomes selected by their authors. The results of the outcomes which approximated most closely to the primary outcome for this review were as follows.
In the azathioprine trial there was a median improvement in the Neuropathy Impairment Scale (scale range 0 to 280) after nine months of 29 points (range 49 points worse to 84 points better) in the azathioprine and prednisone treated participants compared with 30 points worse (range 20 points worse to 104 points better) in the prednisone alone group. There were no reports of adverse events.
In a cross-over trial of IFN beta-1a with 20 participants, the treatment periods were 12 weeks. The median improvement in the Guy's Neurological Disability Scale (range 1 to 10) was 0.5 grades (interquartile range (IQR) 1.8 grades better to zero grade change) in the IFN beta-1a treatment period and 0.5 grades (IQR 1.8 grades better to 1.0 grade worse) in the placebo treatment period. There were no serious adverse events in either treatment period.
In a parallel group trial of IFN beta-1a with 67 participants, none of the outcomes for this review was available. The trial design involved withdrawal from ongoing IVIg treatment. The primary outcome used by the trial authors was total IVIg dose administered from week 16 to week 32 in the placebo group compared with the IFN beta-1a groups. This was slightly but not significantly lower in the combined IFN beta-1a groups (1.20 g/kg) compared with the placebo group (1.34 g/kg, P = 0.75). There were four participants in the IFN beta-1a group and none in the placebo group with one or more serious adverse events, risk ratio (RR) 4.50 (95% confidence interval (CI) 0.25 to 80.05).
The methotrexate trial had a similar design involving withdrawal from ongoing corticosteroid or IVIg treatment. At the end of the trial (approximately 40 weeks) there was no significant difference in the change in the Overall Neuropathy Limitations Scale, a disability scale (scale range 0 to 12), the median change being 0 (IQR −1 to 0) in the methotrexate group and 0 (IQR −0.75 to 0) in the placebo group. These changes in disability might have been confounded by the reduction in corticosteroid or IVIg dose required by the protocol. There were three participants in the methotrexate group and one in the placebo with one or more serious adverse events, RR 3.56 (95% CI 0.39 to 32.23).