Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside <i>DPYD</i>

Background: The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G &gt; A/rs75017182, c.2846A &gt; T/rs67376798 and c.1679 T &gt; G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity. Methods: Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS. Results: Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C &gt; T, c.1913 T &gt; C, c.1925 T &gt; C, c.506delC, c.731A &gt; C, c.1740 + 1G &gt; T, c.763 − 2A &gt; G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41–11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10−8), however, five variants were suggestive of association (P &lt; 5 × 10−6) with severe toxicity. Conclusions: Results from DPYD exon sequencing and GWAS analysis did not identify additional genetic variants associated with severe toxicity, which suggests that testing for single markers at a population level currently has limited clinical value. Identifying additional variants on an individual level is still promising to explain fluoropyrimidine-related severe toxicity. In addition, studies with larger samples sizes, in more diverse cohorts are needed to identify potential clinically relevant genetic variants related to severe fluoropyrimidine toxicity.</p

Multifocal motor neuropathy in the Netherlands : immunology, genetics and treatment

MMN In a national study on MMN we identified 97 patients. Eighty-eight patients participated in our study. Multivariate analysis showed that axon loss and longer disease duration without IVIg were independent determinants of more severe weakness and disability. IMMUNE PATHOGENESIS Prevalence and specificity of antibodies against single gangliosides and ganglioside complexes in serum were investigated. Anti-ganglioside IgM antibodies in MMN had a surprisingly limited specificity (against GM1, and occasionally against GD1b and GM2). Therefore, we investigated whether anti-ganglioside antibodies also showed limited clonality. Using light chain analysis of anti-GM1 IgM antibodies, we demonstrated that serum anti-GM1 IgM antibodies in the majority of patients with MMN have the same Ig light chain, suggesting that these antibodies are monoclonal. Patients with anti-GM1 IgM antibodies had more disability, more axon loss and more severe weakness compared to patients without anti-GM1 IgM antibodies.These findings support the assumption that antiganglioside IgM antibodies play a role in MMN pathogenesis. It is not clear whether MMN is a ‘classic’ autoimmune disease (AID). Since different AID often co-occur within patients and their families, we studied the prevalence of AID among MMN patients and their families. In a case-control study encompassing 81 MMN patients and 417 first-degree relatives, and 438 controls and 2,377 first-degree relatives we found that AID are more common in MMN patients (11%) compared to controls (5%). We also studied variation in the activity of the classical and lectin pathway of the complement system in MMN patients and controls. We found no difference in activity of both pathways and complement activity was not associated with outcome of MMN. GENETICS The human leukocyte antigen (HLA) locus is highly heterogeneous, and several HLA alleles have been found associated with AID. A case-control study showed that HLA-DRB1*15 is associated with MMN. Although this finding may support the hypothesis that MMN is a classic AID, we did not find increased frequencies of single nucleotide polymorphisms (SNPs) in genes that are common in a number of other AID. TREATMENT Maintenance treatment with IVIg every few weeks is necessary because the beneficial effects only last a few weeks. A cross-sectional descriptive study showed that IVIg treatment at home is time-saving and reduces the number of days missed at work. Home-treatment is safe and more convenient for most patients. Despite its use, the mechanisms of IVIg that underlie its efficacy in MMN have not been studied in detail. Relevant effector mechanisms of IVIg include anti-idiotype effects, and modulation of B-cell and complement function, among others. We compared the complement-activating properties of anti-GM1 IgM antibodies in sera from MMN patients and disease controls. We showed that anti-GM1 IgM antibodies in sera from MMN patients efficiently activate complement in comparison with disease controls. The addition of IVIg reduced complement deposition significantly. IVIg also reduced concentrations of crucial classical pathway components including C1q in sera of MMN patients. IVIg may thus exert both local and systemic effects on the classical route of the complement system, which may contribute to reduced complement deposition in nerves

Multifocal motor neuropathy: Association of anti-GM1 IgM antibodies with clinical features

10.1212/WNL.0b013e3181ff94c2Neurology75221961-1967NEUR

Classical and lectin complement pathway activity in polyneuropathy associated with IgM monoclonal gammopathy

Item does not contain fulltextPolyneuropathy associated with IgM monoclonal gammopathy (IgM-PNP) is a slowly progressive, sensorimotor neuropathy. It is assumed that complement activation contributes to IgM-PNP pathogenesis. We investigated whether innate differences in complement activity of the classical and mannose binding lectin (MBL) pathways are associated with IgM-PNP or its severity. We measured complement activity using ELISA and determined MBL serumc oncentrations and MBL gene polymorphisms in 83 patients and 83 healthy controls. We did not observe differences between IgM-PNP patients and healthy controls nor associations with different disease severities. Differences in innate complement activity are not likely to explain susceptibility to or severity of IgM-PNP

Randomised controlled trial comparing two different intravenous immunoglobulins in chronic inflammatory demyelinating polyradiculoneuropathy

Background Different preparations of intravenous immunoglobulin (IVIg) are considered to have comparable clinical efficacy but this has never been formally investigated. Some patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) report that some IVIg brands are more effective than others. A liquid IVIg preparation is more user friendly and potentially can be infused at a faster rate. Objectives The primary objective was to compare the efficacy of two different IVIg brands in CIDP. The secondary objective was to compare their safety. Methods This was an investigator-initiated multi-centre randomised controlled double-blind trial. Twenty-seven patients with active but stable CIDP treated with their individual stable IVIg (Gammagard S/D) maintenance dose and interval were randomised to receive four infusions of freeze-dried 5% IVIg (Gammagard S/D) or the new liquid 10% IVIg (Kiovig). The overall disability sum score (ODSS) was used as the primary outcome scale. The equivalence margin was defined as a difference of <= 1 point in mean Delta ODSS between treatment groups. Main secondary outcome scales were the MRC sum score and the Vigorimeter. Results Repeated measurements analysis of variance, adjusted for baseline ODSS, showed a clinically insignificant treatment difference of 0.004 (95% CI -0.4 to 0.4). We also found no significant differences in any of the other outcome measures. Besides a lower occurrence of cold shivers in patients randomised to Kiovig (p=0.03), no significant differences were found in the occurrence of adverse events. Conclusions This trial demonstrated equal clinical efficacy between a freeze-dried and a liquid IVIg preparation for maintenance treatment of CID

Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy.

Contains fulltext : 87685.pdf (publisher's version ) (Closed access)OBJECTIVE: Identification and examination of all patients with multifocal motor neuropathy (MMN) in the Netherlands to document the clinical spectrum and response to IV immunoglobulin (IVIg) and to determine correlates of outcome. METHODS: A national cross-sectional descriptive study was performed. Ninety-seven patients were identified; 88 participated. Logistic regression analysis was used to study determinants of outcome. RESULTS: Age at onset was younger in men than in women (38 vs 45 years, p = 0.05). Onset of weakness was in distal arm (61%) or distal leg (34%), and occasionally in the upper arm (5%). Initial diagnosis was motor neuron disease in one-third of patients. Brisk, but not pathologic, reflexes in weakened muscles were found in 8%. Conduction blocks were most frequently detected in the ulnar (80%) and median (77%) nerves, but occasionally only between Erb and axilla (6%), or in the musculocutaneous nerve (1%). Ninety-four percent responded to IVIg therapy: nonresponders had longer disease duration before the first treatment (p = 0.03). Seventy-six percent received IVIg maintenance treatment at the time of this study (median duration 6 years; range 0-17): the median dose increased over the years from 12 to 17 g per week (p or=1 Medical Research Council grade in at least 2 muscle groups without decrease in other muscle groups) in 94% (95% confidence interval, 86.8%-97.4%) of patients