Treatment in chronic immune-mediated neuropathies: A time to start and a time to stop

Chronic inflammatory demyelinating polyneuropathy (CIDP) and multiple motor neuropathy (MMN) are immune mediated neuropathies with a heterogeneous clinical presentation. This makes both the diagnosis and choosing the right treatment strategy challenging. Furthermore, several trails suggest overtreatment in patients with long-term maintenance treatment in CIDP. The aim of this thesis was to identify some of the challenges in treatment and diagnosis of CIDP and MMN, and to explore induction treatment and possible overtreatment in CIDP. In the first part of this thesis, we identified patients who did not meet the mandatory diagnostic criteria but did respond to immunomodulatory treatment. Furthermore, we conducted a diagnostic test accuracy review on IgM anti-GM1 antibody testing and found the test characteristics to be of limited added value. In the second part of this thesis, we performed a literature review showing possible overtreatment with intravenous immunoglobulin (IVIg) maintenance treatment in CIDP patients. Furthermore, we performed a pilot study with combined IVIg en intravenous methylprednisolone as induction treatment showing more than half of the CIDP patients remained clinically stable at one-year follow up. In addition, we present a case series of patients with cutaneous lupus erythematosus as a side effect of long-term IVIg treatment. Finally, we performed a randomized controlled non-inferiority trial, in which we compared IVIg withdrawal with placebo with continuation of IVIg treatment in CIDP patients. We showed that a considerable part of the participants could stop treatment without experiencing deterioration and that IVIg withdrawal is safe

Treatment in chronic immune-mediated neuropathies: A time to start and a time to stop

Chronic inflammatory demyelinating polyneuropathy (CIDP) and multiple motor neuropathy (MMN) are immune mediated neuropathies with a heterogeneous clinical presentation. This makes both the diagnosis and choosing the right treatment strategy challenging. Furthermore, several trails suggest overtreatment in patients with long-term maintenance treatment in CIDP. The aim of this thesis was to identify some of the challenges in treatment and diagnosis of CIDP and MMN, and to explore induction treatment and possible overtreatment in CIDP. In the first part of this thesis, we identified patients who did not meet the mandatory diagnostic criteria but did respond to immunomodulatory treatment. Furthermore, we conducted a diagnostic test accuracy review on IgM anti-GM1 antibody testing and found the test characteristics to be of limited added value. In the second part of this thesis, we performed a literature review showing possible overtreatment with intravenous immunoglobulin (IVIg) maintenance treatment in CIDP patients. Furthermore, we performed a pilot study with combined IVIg en intravenous methylprednisolone as induction treatment showing more than half of the CIDP patients remained clinically stable at one-year follow up. In addition, we present a case series of patients with cutaneous lupus erythematosus as a side effect of long-term IVIg treatment. Finally, we performed a randomized controlled non-inferiority trial, in which we compared IVIg withdrawal with placebo with continuation of IVIg treatment in CIDP patients. We showed that a considerable part of the participants could stop treatment without experiencing deterioration and that IVIg withdrawal is safe

Structures of some acetyl-serine peptides from acetyl-chymotrypsin

IN 1958, two of us1 obtained, by enzymic degradation of acetyl-chymotrypsin labelled with carbon-142, five peptides containing labelled acetyl-groups. Subsequent sequence studies3 have shown that the largest of these peptides has the amino-acid sequence, Gly.Asp.Ser.Gly.Gly.Pro.Leu, identical with that already found4, by degradation of the di-isopropylphosphoryl-enzyme, to surround the reactive serine ; it may reasonably be concluded that the other four peptides contain the sequences Ser.Gly.Gly.Pro.Leu, Asp.Ser.Gly.Gly, Gly.Asp.Ser.Gly and Ser.Gly.Gly, respectively. © 1960 Nature Publishing Group

Assessing deterioration using impairment and functional outcome measures in chronic inflammatory demyelinating polyneuropathy: A post-hoc analysis of the immunoglobulin overtreatment in CIDP trial

It is unclear whether frequently used cutoff values for outcome measures defining minimal clinically important differences (MCIDs) can accurately identify meaningful deterioration in chronic inflammatory demyelinating polyneuropathy (CIDP). We used data from the immunoglobulin overtreatment in CIDP (IOC) trial, in which 60 clinically stable patients with CIDP were randomized to intravenous immunoglobulin (IVIg) withdrawal or continuation. We calculated change scores of the Inflammatory Rasch-Built Overall Disability Scale (I-RODS), grip strength, and Medical Research Council-sum score (MRC-SS) and classified visits based on a treatment anchor (ie, decision to restart/increase treatment after reaching a predefined early endpoint of deterioration). The variability of scores in patients without deterioration was calculated using the limits of agreement. We defined optimized MCIDs for deterioration and specific combinations of MCIDs from different outcome measures, and subsequently calculated the accuracies of the (combined) MCIDs. Substantial variability was found in scores of the I-RODS, grip strength and MRC-SS in patients without deterioration over time, and most MCIDs were within the limits of the variability observed in patients without deterioration. Some MCID cut-offs were insensitive but highly specific for detecting deterioration, for example, the MCID-SE of -1.96 of the I-RODS and -2 point on the MRC-SS. Others were sensitive, but less specific, for example, -4 centiles of the I-RODS. Some combined MCIDs resulted in high specificities and moderate sensitivities. Our results suggest that clinically important deterioration cannot be distinguished from variability over time with currently used MCIDs on the individual level. Combinations of MCIDs might improve the accuracy of determining deterioration, but this needs validation

Vegetation relevés and soil measurements in the Netherlands: the Ecological Conditions Database (EC)

Since its establishment around 1990, the Ecological Conditions Database (EC; GIVD ID EU-00-006) has been accumulating vegetation relevés from the Netherlands, each accompanied by at least one abiotic soil measurement (e.g. pH or nutrient availability). On 1-1-2010, the database contained 8,229 relevés, covering the period from 1936 to 2009, and representing contributions from 110 authors. The most frequently measured soil parameter is pH, with well over 5,000 entries. All the data in the database are subjected to ISO 9001 quality control. The database can be used as the starting point for estimating plant species responses to a range of abiotic variables, such as pH, groundwater table, or nitrate concentration, and for vegetation modelling (model parameterisation and validation)

Withdrawal of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy

Intravenous immunoglobulins are an efficacious treatment for chronic inflammatory demyelinating polyradiculoneuropathy. Biomarkers for disease activity are lacking, making the need for ongoing treatment difficult to assess, leading to potential overtreatment and high health-care costs. Our objective was to determine whether intravenous immunoglobulin withdrawal is non-inferior to continuing intravenous immunoglobulin treatment and to determine how often patients are overtreated.We performed a randomized, double-blind, intravenous immunoglobulin-controlled non-inferiority trial in seven centres in the Netherlands (Trial registration: ISRCTN 13637698; www.isrctn.com/ISRCTN13637698) . Adults with clinically stable chronic inflammatory demyelinating polyradiculoneuropathy using intravenous immunoglobulin maintenance treatment for at least 6 months were included. Patients received either intravenous immunoglobulin withdrawal (placebo) as investigational treatment or continuation of intravenous immunoglobulin treatment (control). The primary outcome was the mean change in logit scores from baseline to 24-week follow-up on the patient-reported Inflammatory Rasch-Overall Disability Scale. The non-inferiority margin was predefined as between-group difference in mean change scores of -0.65. Patients who deteriorated could reach a relapse end point according to predefined criteria. Patients with a relapse end point after intravenous immunoglobulin withdrawal entered a restabilization phase. All patients from the withdrawal group who remained stable were included in an openlabel extension phase of 52 weeks.We included 60 patients, of whom 29 were randomized to intravenous immunoglobulin withdrawal and 31 to continuation of treatment. The mean age was 58 years (SD 14.7) and 67% was male. The between-group difference in mean change Inflammatory Rasch-Overall Disability Scale scores was -0.47 (95% CI -1.24 to 0.31), indicating that non-inferiority of intravenous immunoglobulin withdrawal could not be established. In the intravenous immunoglobulin withdrawal group, 41% remained stable for 24 weeks, compared to 58% in the intravenous immunoglobulin continuation group (-17%; 95% CI -39 to 8). Of the intravenous immunoglobulin withdrawal group, 28% remained stable at the end of the extension phase. Of the patients in the restabilization phase, 94% restabilized within 12 weeks. In conclusion, it remains inconclusive whether intravenous immunoglobulin withdrawal is non-inferior compared to continuing treatment, partly due to larger than expected confidence intervals leading to an underpowered study. Despite these limitations, a considerable proportion of patients could stop treatment and almost all patients who relapsed were restabilized quickly. Unexpectedly, a high proportion of intravenous immunoglobulin-treated patients experienced a relapse end point, emphasizing the need for more objective measures for disease activity in future trials, as the patient-reported outcome measures might not have been able to identify true relapses reliably. Overall, this study suggests that withdrawal attempts are safe and should be performed regularly in clinically stable patients