primary outcome:
Immunotherapy for IgM anti‐myelin‐associated glycoprotein paraprotein‐associated peripheral neuropathies
Predefined primary outcome measures were numbers of participants improved in disability at six months after randomisation assessed with either or both of:
(a) the Neuropathy Impairment Scale (NIS) (Dyck 1980; Dyck 2005) by at least 10% (maximum score 244);
(b) the modified Rankin Scale (mRS) (Bamford 1989) (scale 0 to 6).We selected the NIS and mRS as primary outcome measures, as we considered them to be broad, commonly‐used scores that were potentially easy to retrospectively derive from collected data. We predefined six months as the favoured time point for re‐evaluation on the basis that IgM anti‐MAG paraprotein‐associated neuropathy is a chronic and slowly progressive disorder. A reduction in either score indicates improvement and as there is no published minimum clinically important difference for the NIS, we defined a 10% change as improvement.One trial with 22 participants (Comi 2002), of IVIg versus placebo in IgM paraprotein‐associated neuropathy used the modified Rankin Scale (mRS). However, this was a short trial and the investigators only measured the primary outcome at two and four weeks, not at six months. Eleven of 22 participants had anti‐MAG antibodies but the data concerning the anti‐MAG participant subgroup were not available. At two weeks, the mRS score showed a significant improvement with IVIg (‐0.38, standard deviation (SD) 0.58) over placebo (+0.19, SD 0.51) at two weeks (P = 0.008), a difference that may not be clinically significant. No significant difference between the groups was present at four weeks.The primary outcome of Comi 2002 was the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score at four weeks. This was not one of our prespecified outcome measures (see Discussion). After two weeks, the INCAT disability score did not change significantly; there was no difference between the groups and no evidence of a carry‐over effect. After four weeks, the INCAT disability score decreased by a mean of 0.55 (SD 0.67) grades in the IVIg period (P = 0.001), with no significant change (mean 0.05 (SD 0.90)) in the placebo period. Only the mean difference (MD) between the treatment effects in the two four‐week periods was significant (0.5 of a grade, 95% confidence interval (CI) 0.00 to 1.00).The mRS was not assessed. The Neuropathy Impairment Scale (NIS) was the primary outcome in both studies involving interferon alfa‐2a (referred to as the Clinical Neuropathy Disability Score (CNDS), a scale derived with minor modifications from the NIS, maximum score 93 (higher scores indicate greater disability)). In the initial randomised but open parallel‐group study of interferon alfa‐2a versus IVIg (Mariette 1997), participants in the IVIg group worsened by a mean of 2.3 (SD 7.6) points on the NIS at six months, and those in the interferon alfa‐2a group improved by 7.5 (11.1) points, a MD of 9.80 (95% CI 1.46 to 18.14, n = 20) in favour of interferon alfa‐2a (Analysis 1.1). However, Mariette 2000 (n = 24), a randomised and blinded trial of interferon alfa‐2a versus placebo at low risk of bias, failed to confirm the beneficial effect of interferon alfa‐2a in the primary outcome at six months (Analysis 2.1).In a comparison of chlorambucil and plasma exchange versus chlorambucil alone in IgM paraprotein‐associated neuropathy, the NIS at four months showed no statistically significant difference in outcome (Oksenhendler 1995). The trialists assessed neither the NIS nor the mRS at the six‐month time point specified for this review. Data were not available for the anti‐MAG subgroup alone, as participants with anti‐MAG activity were not differentiated from those without.These two studies included neither the NIS nor the mRS as outcomes. The INCAT leg score reported in Dalakas 2009 corresponds broadly to the mRS and thus we used this in our analysis both as a continuous and a dichotomous outcome. For the dichotomous improvement we have compared the leg score at eight months from Dalakas 2009 with the dichotomous complete INCAT score at 12 months from Léger 2013 (Analysis 3.1; Figure 3). The RR for improvement was 3.51, 95% CI 1.30 to 9.45 (I2 = 0%, 73 participants). We will perform a six‐month meta‐analysis if other studies become available. Using the published eight‐month data from Dalakas 2009 and 12‐month data from Léger 2013, the mean improvement in the INCAT leg disability score (MD ‐0.45, 95% CI ‐0.85 to ‐0.05; I2 = 0%) was statistically significant, whether the INCAT 0‐score participant from Dalakas 2009 was included in the analysis or not (summary of findings Table for the main comparison; Analysis 3.2). Participant‐level data obtained for nine‐month improvement from Léger 2013 (not published), which are at a more comparable time point to Dalakas 2009, give a MD of ‐0.33, 95% CI ‐0.73 to 0.07 (I2 = 0%, 70 participants) in the same direction as the longer time point but including the possibility of no effect (Analysis 3.3).(Note: in the published paper of Dalakas 2009 there is a discrepancy between the data for the INCAT leg score in the text and in the published table. We checked the data with the trial authors who gave verbal clarification and we included the correct figures. No recorded trial data were made available.)The mRS at six months was included as one of the outcomes of phase one of this trial, the only disability data that could be included in this review. At six months a (barely) significant improvement in the mean mRS was present, with a MD of ‐0.31 points (95% CI ‐0.61 to ‐0.01; 34 participants; Analysis 4.1), with no significant difference in the number of participants improved at six months when we extracted the dichotomous data from the dataset provided by the authors (3/16 improved with cyclophosphamide and prednisolone combination versus 1/19 with placebo, RR 3.56, 95% CI 0.41 to 30.99; 35 participants; Analysis 4.2.