Background: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS... Show moreBackground: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs. Methods: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies. Results: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p < 0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p < 0.001 and p < 0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2-31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%). Conclusion: IMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild. Show less
BackgroundPatients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV... Show moreBackgroundPatients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs.MethodsIMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies.ResultsIn total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p < 0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p < 0.001 and p < 0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2–31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%).ConclusionIMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild. Show less
For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease ac-tivity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2... Show moreFor patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease ac-tivity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective obser-vational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/ 2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Alto-gether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity. Show less
For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2... Show moreFor patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective observational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Altogether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity. Show less
Pompe disease is an inherited metabolic myopathy caused by deficiency of acid alpha-glucosidase (GAA), resulting in lysosomal glycogen accumulation. Residual GAA enzyme activity affects disease... Show morePompe disease is an inherited metabolic myopathy caused by deficiency of acid alpha-glucosidase (GAA), resulting in lysosomal glycogen accumulation. Residual GAA enzyme activity affects disease onset and severity, although other factors, including dysregulation of cytoplasmic glycogen metabolism, are suspected to modulate the disease course. In this study, performed in mice and patient biopsies, we found elevated protein levels of enzymes involved in glucose uptake and cytoplasmic glycogen synthesis in skeletal muscle from mice with Pompe disease, including glycogenin (GYG1), glycogen synthase (GYS1), glucose transporter 4 (GLUT4), glycogen branching enzyme 1 (GBE1), and UDP-glucose pyrophosphorylase (UGP2). Expression levels were elevated before the loss of muscle mass and function. For first time, quantitative mass spectrometry in skeletal muscle biopsies from five adult patients with Pompe disease showed increased expression of GBE1 protein relative to healthy controls at the group level. Paired analysis of individual patients who responded well to treatment with enzyme replacement therapy (ERT) showed reduction of GYS1, GYG1, and GBE1 in all patients after start of ERT compared to baseline. These results indicate that metabolic changes precede muscle wasting in Pompe disease, and imply a positive feedforward loop in Pompe disease, in which lysosomal glycogen accumulation promotes cytoplasmic glycogen synthesis and glucose uptake, resulting in aggravation of the disease phenotype. Show less
Objectives: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on... Show moreObjectives: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on immunosuppressants and controls, and to investigate determinants for breakthrough infections. Methods: Data were used from an ongoing national prospective multicentre cohort study on SARS-CoV-2 vaccination responses in patients with IMID in the Netherlands (Target-to-B! (T2B!) study). Patients wih IMID on immunosuppressants and controls (patients with IMID not on immunosuppressants and healthy controls) who completed primary immunisation were included. The observation period was between 1 January 2022 and 1 April 2022, during which the SARS-CoV-2 omicron (BA.1 and BA.2 subvariant) was dominant. A SARS-CoV-2 breakthrough infection was defined as a reported positive PCR and/or antigen test at least 14 days after primary immunisation. A multivariate logistic regression model was used to investigate determinants. Results: 1593 patients with IMID on immunosuppressants and 579 controls were included. The cumulative incidence of breakthrough infections was 472/1593 (29.6%; 95% CI 27% to 32%) in patients with IMID on immunosuppressants and 181/579 (31.3%; 95% CI 28% to 35%) in controls (p=0.42). Three (0.5%) participants had severe disease. Seroconversion after primary immunisation (relative risk, RR 0.71; 95% CI 0.52 to 0.96), additional vaccinations (RR 0.61; 95% CI 0.49 to 0.76) and a prior SARS-CoV-2 infection (RR 0.60; 95% CI 0.48 to 0.75) were associated with decreased risk of breakthrough infection. Conclusions: The cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections was high, but similar between patients with IMID on immunosuppressants and controls, and disease severity was mostly mild. Additional vaccinations and prior SARS-CoV-2 infections may reduce the incidence of breakthrough infections. Show less
Background: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants,... Show moreBackground: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants, but clinical data on breakthrough infections are still scarce. The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between patients with immune-mediated inflammatory diseases using immunosuppressants, and controls (patients with immune-mediated inflammatory diseases not taking immunosuppressants and healthy controls) who had received full COVID-19 vaccinations. The secondary objective was to explore determinants of breakthrough infections of the delta (B.1.617.2) variant of SARS-CoV-2, including humoral immune responses after vaccination. Methods: In this substudy, we pooled data collected in two large ongoing prospective multicentre cohort studies conducted in the Netherlands (Target to-B! [T2B!] study and Amsterdam Rheumatology Center COVID [ARC-COVID] study). Both studies recruited adult patients (age >= 18 years) with immune-mediated inflammatory diseases and healthy controls. We sourced clinical data from standardised electronic case record forms, digital questionnaires, and medical files. We only included individuals who were vaccinated against SARS-CoV-2. For T2B!, participants were recruited between Feb 2 and Aug 1, 2021, and for ARC-COVID, participants were recruited between April 26, 2020, and March 1, 2021. In this study we assessed data on breakthrough infections collected between July 1 and Dec 15, 2021, a period in which the delta SARS-CoV-2 variant was the dominant variant in the Netherlands. We defined a SARS-CoV-2 breakthrough infection as a PCR-confirmed or antigen test-confirmed SARS-CoV-2 infection that occurred at least 14 days after vaccination. All breakthrough infections during this period were assumed to be due to the delta variant due to its dominance during the study period. We analysed post-vaccination serum samples for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC-COVID study only). We used multivariable logistic regression analyses to explore potential clinical and humoral determinants associated with the odds of breakthrough infections. The T2B! study is registered with the Dutch Trial Register, Trial ID NL8900, and the ARC-COVID study is registered with Dutch Trial Register, trial ID NL8513. Findings: We included 3207 patients with immune-mediated inflammatory diseases who receive immunosuppressants, and 1807 controls (985 patients with immune-mediated inflammatory disease not on immunosuppressants and 822 healthy controls). Among patients receiving immunosuppressants, mean age was 53 years (SD 14), 2042 (64%) of 3207 were female and 1165 (36%) were male; among patients not receiving immunosuppressants, mean age was 54 years (SD 14), 598 (61%) of 985 were female and 387 (39%) were male; and among healthy controls, mean age was 57 years (SD 13), 549 (67%) of 822 were female and 273 (33%) were male. The cumulative incidence of PCR-test or antigen-test confirmed SARS-CoV-2 breakthrough infections was similar in patients on immunosuppressants (148 of 3207; 4.6% [95% CI 3.9-5.4]), patients not on immunosuppressants (52 of 985; 5.3% [95% CI 4.0-6.9]), and healthy controls (33 of 822; 4.0% [95% CI 2.8-5.6]). There was no difference in the odds of breakthrough infection for patients with immune-mediate inflammatory disease on immunosuppressants versus combined controls (ie, patients not on immunosuppressants and healthy controls; adjusted odds ratio 0.88 [95% CI 0.66-1.18]). Seroconversion after vaccination (odds ratio 0.58 [95% CI 0.34-0.98]; T2B! cohort only) and SARS-CoV-2 infection before vaccination (0.34 [0.18-0.56]) were associated with a lower odds of breakthrough infections. Interpretation: The incidence and severity of SARS-CoV-2 breakthrough infections in patients with immune-mediated inflammatory diseases on immunosuppressants was similar to that in controls. However, caution might still be warranted for those on anti-CD20 therapy and those with traditional risk factors. Copyright (C) 2022 Elsevier Ltd. All rights reserved. Show less
Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific... Show moreBackground: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific immunosuppressants. Diseaseoverarching studies, and data on recall responses and third vaccinations are scarce. Our primary objective was to investigate the effects of immunosuppressive monotherapies on the humoral immune response after SARS-CoV-2 vaccination in patients with prevalent immune-mediated inflammatory disorders. Methods: We did a cohort study in participants treated in outpatient clinics in seven university hospitals and one rheumatology treatment centre in the Netherlands as well as participants included in two national cohort studies on COVID-19-related disease severity. We included patients aged older than 18 years, diagnosed with any of the prespecified immune-mediated inflammatory disorders, who were able to understand and complete questionnaires in Dutch. Participants with immune-mediated inflammatory disorders who were not on systemic immunosuppressants and healthy participants were included as controls. Anti-receptor binding domain IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses-ie, vaccination after previous SARS-CoV-2 infection-were studied as a proxy for recall responses. Findings: Between Feb 2 and Aug 1, 2021, we included 3222 participants in our cohort. Sera from 2339 participants, 1869 without and 470 participants with previous SARS-CoV-2 infection were analysed (mean age 49.9 years [SD 13 center dot 7]; 1470 [62.8%] females and 869 [37.2%] males). Humoral responses did not differ between disorders. Anti-CD20 therapy, sphingosine 1-phosphate receptor (S1P) modulators, and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks for reaching seroconversion following standard vaccination (0.32 [95% CI 0.19-0.49] for anti-CD20 therapy, 0.35 [0.21-0.55] for S1P modulators, and 0.61 [0.40-0.90] for mycophenolate mofetil combined with corticosteroids). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments (from 52.6% after the second vaccination to 89.5% after the third) but not significantly for anti-CD20 therapies (from 36.8% to 45.6%) and S1P modulators (from 35.5% to 48.4%). Most other immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment. Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants. After standard vaccination regimens, patients with immune-mediated inflammatory disorders taking most immunosuppressants show similar seroconversion to controls, although antibody titres might be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate to loss of (short-term) protection. In patients on immunosuppressants showing poor humoral responses after standard vaccination regimens, a third vaccination resulted in additional seroconversion in patients taking mycophenolate mofetil combination treatments, whereas the effect of a third vaccination in patients on anti-CD20 therapy and S1P modulators was limited. Copyright (C) 2022 Elsevier Ltd. All rights reserved. Show less
Background: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following... Show moreBackground: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs).Methods: Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life.Results: In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn's disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8-59.8) of patients after the first vaccination, 61.5% (95% CI 59.2-63.7) after the second vaccination and 58% (95% CI 55.3-60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3-9.1), 7.4% (95% CI 6.2-8.7) and 6.8% (95% CI 5.4-8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (<0.7%).Female sex (aRR 1.43, 95% CI 1.32-1.56), age below 50 (aRR 1.14, 95% CI 1.06-1.23), a preceding SARS-CoV-2 infection (aRR 1.14, 95% CI 1.01-1.29) and having an IMID (aRR 1.16, 95% CI 1.01-1.34) were associated with increased risk of rAEs following a vaccination. Compared to the second vaccination, the first vaccination was associated with a lower risk of rAEs (aRR 0.92, 95% CI 0.84-0.99) while a third vaccination was not associated with increased risk on rAEs (aRR 0.93, 95% CI 0.84-1.02). BNT162b2 vaccines were associated with lower risk on rAEs compared to CX-024414 (aRR 0.86, 95% CI 0.80-0.93).Conclusions: A third SARS-CoV-2 vaccination was not associated with increased risk of rAEs in IMID patients compared to the second vaccination. Patients with an IMID have a modestly increased risk of rAEs after vaccination when compared to controls. Most AEs are resolved within 7 days; hospital admissions and allergic reactions were uncommon. Show less
Objective To compare the disease course in patients with mild Guillain-Barre syndrome (GBS) who were treated with intravenous immunoglobulin (IVIg) or supportive care only.Methods We selected... Show moreObjective To compare the disease course in patients with mild Guillain-Barre syndrome (GBS) who were treated with intravenous immunoglobulin (IVIg) or supportive care only.Methods We selected patients from the prospective observational International GBS Outcome Study (IGOS) who were able to walk independently at study entry (mild GBS), treated with one IVIg course or supportive care. The primary endpoint was the GBS disability score four weeks after study entry, assessed by multivariable ordinal regression analysis.Results Of 188 eligible patients, 148 (79%) were treated with IVIg and 40 (21%) with supportive care. The IVIg group was more disabled at baseline. IVIg treatment was not associated with lower GBS disability scores at 4 weeks (adjusted OR (aOR) 1.62, 95% CI 0.63 to 4.13). Nearly all secondary endpoints showed no benefit from IVIg, although the time to regain full muscle strength was shorter (28 vs 56 days, p=0.03) and reported pain at 26 weeks was lower (n=26/121, 22% vs n=12/30, 40%, p=0.04) in the IVIg treated patients. In the subanalysis with persistent mild GBS in the first 2 weeks, the aOR for a lower GBS disability score at 4 weeks was 2.32 (95% CI 0.76 to 7.13). At 1 year, 40% of all patients had residual symptoms.Conclusion In patients with mild GBS, one course of IVIg did not improve the overall disease course. The certainty of this conclusion is limited by confounding factors, selection bias and wide confidence limits. Residual symptoms were often present after one year, indicating the need for better treatments in mild GBS. Show less
Walgaard, C.; Jacobs, B.C.; Lingsma, H.F.; Steyerberg, E.W.; Berg, B. van den; Doets, A.Y.; ... ; Dutch GBS Study Grp 2021
Background Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients... Show moreBackground Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barre syndrome with a predicted poor outcome.Methods In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (>= 12 years) with Guillain-Barre syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of >= 6) according to the modified Erasmus Guillain-Barre syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7-9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barre syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis.Findings Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barre syndrome disability score at 4 weeks was 1.4 (95% CI 0.6-3.3; p=0.45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13-24 weeks after randomisation).Interpretation Our study does not provide evidence that patients with Guillain-Barre syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barre syndrome. Funding Prinses Beatrix Spierfonds and Sanquin Plasma Products. Copyright (C) 2021 Elsevier Ltd. All rights reserved. Show less
Kuitwaard, K.; Doorn, P.A. van; Bengrine, T.; Rijs, W. van; Baas, F.; Nagelkerke, S.Q.; ... ; Huizinga, R. 2021
Background and purpose Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a clinical and electrophysiological heterogeneous immune-mediated polyneuropathy. Intravenous... Show moreBackground and purpose Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a clinical and electrophysiological heterogeneous immune-mediated polyneuropathy. Intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange are proven effective treatments for CIDP. The clinical response to IVIg is variable between patients and currently unexplained. Finding biomarkers related to treatment response can help to understand the diversity of CIDP and personalise treatment choice.Methods We investigated whether genetic variation between patients may explain some of these differences in treatment response. Based on previous publications, we selected six candidate genes that might affect immune and axonal functions, IVIg metabolism, and treatment response in CIDP. Genetic variants were assessed in 172 CIDP patients treated with at least one course of IVIg (2 g/kg). A response to IVIg was defined by >= 1 grade improvement on the modified Rankin Scale. Blood samples were tested for variations in CNTN2, PRF1, FCGRT, FCGR2B, GJB1, and SH2D2A genes.Results In univariate analysis, patients with the FCGR2B promoter variant 2B.4/2B.1 responded more often to IVIg than patients with the 2B.1/2B.1 variant (odds ratio [OR] = 6.9, 95% confidence interval [CI] = 1.6-30; p = 0.003). Patients with the p.(Ala91Val) variant of PRF1 were less often IVIg responsive (OR = 0.34, 95% CI = 0.13-0.91; p = 0.038). In multivariate analysis, both PRF1 and FCGR2B showed discriminative ability to predict the chance of IVIg response (area under the curve = 0.67).Conclusions Variations in PRF1 and the promoter region of FCGR2B are associated with the response to IVIg in CIDP. These findings, which require validation, are a first step towards the understanding of the heterogeneity in the treatment response in CIDP. Show less
Bechakra, M.; Nieuwenhoff, M.D.; Rosmalen, J. van; Groeneveld, G.J.; Huygen, F.J.P.M.; Zeeuw, C.I. de; ... ; Jongen, J.L.M. 2020
Consistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and... Show moreConsistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and skin biopsies processed for PGP9.5 and CGRP immunohistochemistry from patients with bortezomib-induced peripheral neuropathy (BiPN; n = 22), painful diabetic neuropathy (PDN; n = 16), chronic idiopathic axonal polyneuropathy (CIAP; n = 16) and 17 age -matched healthy volunteers. Duration of neuropathic symptoms was significantly shorter in patients with BiPN in comparison with PDN and CLAP patients. BiPN was characterized by a significant increase in epidermal axonal swellings and upper dermis nerve fiber densities (UDNFD) and a decrease in subepidermal nerve fiber densities (SENFD) of PGP9.5-positive fibers and of PGP9.5 containing structures that did not show CGRP labeling, presumably non-peptidergic fibers. In PDN and CIAP patients, intraepidermal nerve fiber densities (IENFD) and SENFD of PGP9.5-positive and of non-peptidergic fibers were decreased in comparison with healthy volunteers. Significant unadjusted associations between LENFD and SENFD of CGRP-positive, i.e. peptidergic, fibers and the MPQ sensory-discriminative, as well as between UDNFD of PGP9.5-positive fibers and the MPQ evaluative/affective component of neuropathic pain, were found in BiPN and CIAP patients. No significant associations were found in PDN patients. Cutaneous innervation changes in BiPN confirm characteristic features of early, whereas those in CIAP and PDN are in line with late forms of neuropathic pathology. Our results allude to a distinct role for non-peptidergic nociceptors in BiPN and CIAP patients. The lack of significant associations in PDN may be caused by mixed ischemic and purely neuropathic pain pathology. Show less
