Search

Patients with immune-mediated inflammatory diseases (IMIDs) may have impaired initial humoral responses after SARS-CoV-2 vaccination depending on the type of immunosuppression (ISP) used.1 It is largely unknown how antibody titres develop over time and whether it is needed to adjust timing of booster campaigns for patients with IMID.

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-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.

ObjectivesTo 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.MethodsData 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.Results1593 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.ConclusionsThe 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.

Item does not contain fulltext INTRODUCTION: Differentiating multifocal motor neuropathy (MMN) from amyotrophic lateral sclerosis (ALS) is important, as MMN is a difficult, but treatable disorder. METHODS: We studied peripheral nerve imaging techniques in differentiating MMN from ALS by measuring the cross-sectional area (CSA) of the median and ulnar nerves in the forearms using high resolution ultrasound (HRUS) and MRI. RESULTS: HRUS CSA values of the median nerve in the forearm (P = 0.002) and the ulnar nerve distal to the sulcus (P = 0.009) were significantly enlarged in patients with MMN. There was a positive correlation between CSA as measured with HRUS and MRI (Spearman rho 0.60; P < 0.001). CONCLUSIONS: Peripheral nerve imaging is a potentially powerful technique to distinguish MMN from ALS. Muscle Nerve, 2016 Muscle Nerve 54: 1133-1135, 2016.

Objective: Achieving long-term remission after a limited more intense treatment period would prevent prolonged use of corticosteroids or IV immunoglobulin (IVIg) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In this prospective cohort study we present long-term follow-up data on patients included in a multicenter randomized controlled trial comparing 6 monthly pulses of dexamethasone with 8 months of daily prednisolone. Methods: Treatment effect was assessed with the Inflammatory Neuropathy Cause and Treatment disability scale and the Rivermead Mobility Index and was categorized using the CIDP Disease Activity Status (CDAS) scale. Results: By March 2011, 39 out of 40 patients were included with a median follow-up of 4.5 years. Cure (>5 years off treatment) or remission according to the CDAS criteria after 1 or 2 courses of pulsed dexamethasone or daily prednisolone was achieved in 10 out of 39 patients (26%). Half of the patients who were in remission after initial treatment experienced a relapse (median treatment-free interval: 17.5 months for dexamethasone, 11 months for prednisolone). Alternative diagnosis was made in 7 out of 12 (58%) who did not respond to any therapy and in none of the treatment-responsive patients. Conclusions: Cure or long-term remission can be achieved in about one-quarter of patients with CIDP after 1 or 2 courses of pulsed dexamethasone or 8-month daily prednisolone. In treatment-nonresponsive patients, the diagnosis CIDP should be reconsidered. Classification of Evidence: This study provides Class IV evidence that pulsed dexamethasone or 8-month daily prednisolone can lead to long-term remission in CIDP. Neurology (R) 2012;78:1079-1084

Item does not contain fulltext Mutations in the valosin-containing protein (VCP) gene were recently reported to be the cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases. VCP mutations are known to cause inclusion body myopathy (IBM) with Paget's disease (PDB) and frontotemporal dementia (FTD). The presence of VCP mutations in patients with sporadic ALS, sporadic ALS-FTD, and progressive muscular atrophy (PMA), a known clinical mimic of inclusion body myopathy, is not known. To determine the identity and frequency of VCP mutations we screened a cohort of 93 familial ALS, 754 sporadic ALS, 58 sporadic ALS-FTD, and 264 progressive muscular atrophy patients for mutations in the VCP gene. Two nonsynonymous mutations were detected; 1 known mutation (p.R159H) in a patient with familial ALS with several family members suffering from FTD, and 1 mutation (p.I114V) in a patient with sporadic ALS. Conservation analysis and protein prediction software indicate the p.I114V mutation to be a rare benign polymorphism. VCP mutations are a rare cause of familial ALS. The role of VCP mutations in sporadic ALS, if present, appears limited. 01 april 2012

The capacity of ganglioside-specific autoantibodies to recruit leukocyte effector functions was studied. Serum samples from 87 patients with Guillain–Barré (GBS) or Miller Fisher syndrome (MFS), containing GM1-, GQ1b-, or GD1b-specific IgG or IgA, were tested for leukocyte activating capacity. Ganglioside-specific IgG antibodies generally induced leukocyte activation, irrespective of specificity. The magnitude of leukocyte degranulation correlated with GM1- and GQ1b-specific IgG titers, but not with disease severity. Finally, GM1- specific IgA activated leukocytes through the IgA receptor, FcαRI (CD89). Therefore, both ganglioside-specific IgG and IgA can recruit leukocyte effector functions, which may be relevant in the pathogenesis of GBS and MFS. © 2006 Elsevier B.V. All rights reserved. Keywords: Guillain–Barré syndrome; Autoantibodies; Pathogenicity; Gangliosides; FcγR

Patients with neuromuscular diseases (NMDs) suffer from respiratory muscle weakness, resulting in respiratory failure for which patients require mechanical ventilation. The weak cough in NMDs causes chest infections. There is limited evidence on the efficacy of interventions to prevent and treat these problems and knowledge about the natural history of respiratory problems in NMDs is incomplete. The first part of this PhD thesis describes the natural history in patients with the NMD spinal muscular atrophy (SMA), a severe hereditary NMD for which genetic treatments have been introduced recently. We showed that progressive respiratory muscle weakness followed by progressive lung function restriction characterizes SMA. More severely affected patients had more severe respiratory muscle weakness and lung function restriction. Hyperventilation was often observed in patients with SMA, which rapidly changed to insufficient ventilation the year before patients required mechanical ventilation. We observed no accelerated lung function decline prior to respiratory failure. The second part of this PhD thesis studies the evidence for supportive treatments in patients with NMDs. Patients with weak cough are supported with cough augmenting treatments such as air stacking or mechanical insufflation-exsufflation (MI-E). , thereby aiming to reduce the number of chest infections. A systematic review of the literature showed no evidence that daily MI-E treatment reduces the number of chest infections or hospital admissions. We retrospectively observed less chest infections and a major reduction of admission days in children the years following MI-E introduction. We prospectively studied the effect of air stacking and MI-E on lung function. We observed increased lung volumes immediately after air stacking or MI-E treatment. This effect was prolonged up to one hour after MI-E application. We investigated the role of scoliosis (surgery) on lung function and did not find evidence for stabilization of lung function after scoliosis surgery. Lung function testing plays an important role in the assessment of possible respiratory failure in children with NMDs. However, obtaining reliable test results is a major challenge. In the last part of this PhD thesis we studied the relation between oscillometry and lung function results. We observed a non-linear relation between oscillometry and lung function results in children with NMDs.

Fatigability has emerged as an important dimension of physical impairment reported by patients with the spinal muscular atrophy (SMA). Fatigability, for example occurring during walking, writing or combing hair, is defined as the inability to continuously perform a task on the same power output even though someone is physically capable to perform the specific task. The main objective of this thesis was to gain more insights in peripheral factors possibly underlying fatigability of skeletal muscles in patients with SMA. The development of a set of three endurance tests was the first step to facilitate studies on fatigability in ambulant as well as non-ambulant patients with SMA. During these endurance tests, we examined the presence of and the possibility to improve muscle activation. Our results indicated the availability of reserve capacity in muscles of individual patients which can be used when fatigability occurs. Furthermore, we found enhanced muscle reserve capacity in patients treated with pyridostigmine compared to a placebo. Next, we investigated skeletal muscle morphology, mitochondrial function and muscle blood supply. Quantitative MRI analyses of upper arm muscles showed to be a feasible method to map disease state of remaining muscle tissue. Muscle fat infiltration and a shift in myofiber composition explained muscle weakness in upper arms of patients with SMA. In addition, MR spectroscopy during arm cycling exercise turned out to be a promising method to map upper arm myofiber composition and muscle metabolism in patients with SMA. In conclusion, we found no evidence for the contribution of muscle metabolism and muscle blood supply as primary limiting factors to fatigability in patients with SMA.

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by progressive muscle weakness and is the leading genetic cause of infant death and disability in childhood. Its prognosis is now being altered by multiple treatments. In order to justify the burden and risks of treatment, there is a need for biomarkers that can identify early treatment response, or the lack thereof. Such a potential biomarker is quantitative MR imaging. This thesis describes multiple MR studies performed in children and adults with SMA. First, quantitative MR markers have been used to describe muscle and nerve characteristics in people with SMA of varying disease type, disease severity and age. Subsequently, a longitudinal study showed that MRI is able to track subclinical disease progression. This study is particularly valuable as future imaging studies on natural disease progression in treatment-naïve patients will become increasingly unlikely. Moreover, when used in the monitoring of young children that received treatment with nusinersen, a characteristic pattern in of fat infiltration emerged that seems to match those who improved under treatment. These preliminary findings could be an indicator of treatment response. This thesis concludes that quantitative muscle MRI can serve as a biomarker for natural disease progression and for treatment effects. Together, these studies provide benchmarks for future projects that would further contribute to our understanding of SMA.

This thesis focuses on the characteristics of chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) evaluated in multiple MRI-studies. Possible improvements of assessment of brachial plexus MRI in diagnosis of CIDP and MMN has been described, as well as an evaluation of quantitative MRI to study pathophysiology. Finally, quantitative MRI has been studied to serve as a potential biomarker to predict disease course and treatment response. The diagnostic value of brachial plexus MRI for the diagnosis of CIDP can be improved by using a quantitative assessment method. The method described in this thesis is reliable and has an acceptable test characteristics. In particular for patients with CIDP MRI may be of added value, especially when nerve conduction studies do not fulfil the electrodiagnostic criteria for CIDP and nerve ultrasound shows no nerve thickening. Quantitative MRI, such as diffusion tensor imaging, has been evaluated to study differences in quantitative diffusion parameters between CIDP and MMN. The differences found can be related to differences in underlying pathophysiological mechanisms. Finally, diffusion tensor imaging has been explored as a biomarker to predict disease course and treatment response in a longitudinal study. Differences in diffusion parameters have been found in patients with CIDP after one-year follow-up. However, these changes over time do not seem to correlate to clinical data.

Hereditary proximal spinal muscular atrophy (SMA) is a severe hereditary neuromuscular disorder, which usually presents in infancy or (early) childhood. SMA is caused by loss of SMN1 gene function, leading to a deficiency of SMN protein. The SMN2 gene in the human genome partially compensates for SMN1 loss, but insufficiently to prevent pathology. As a result of the SMN protein deficiency, patients suffer from progressive loss of bulbar and spinal cord alpha motor neurons. This causes progressive muscular weakness in patients. Four main SMA types of varying disease severity are distinguished, primarily based upon highest achieved motor function during childhood. SMA type 1 is the most common and most severe form, with a symptom onset in infancy. Infants do not learn to sit without support and without treatment, survival is severely shortened. SMA types 2 and 3 are characterized by an onset in childhood. Patients with type 2 learn to sit without support but not walk, whereas patients with type 3 also learn to walk without support. SMA type 4 is a rare, adult-onset form of SMA. The natural history of SMA is characterized by a progressive decline of muscle strength, motor abilities, and lung function. Until recently, no therapies were available for SMA. In the past couple of years, however, the prospect for patients with SMA has changed considerably following the introduction of several genetic therapies. These therapies improve life expectancy and motor function in infants and young children with SMA in the shorter term. Whether these therapies also work in the longer-term and whether they are effective for older children and adults remains to be elucidated. To further study possible therapy efficacy, but also further improve care and counselling for patients and caregivers, it is important to further delineate the natural history of SMA, as it had not been fully studied prior to this thesis, specifically not for older children and adults with SMA. Most studies in the past decades had focused on infants and younger children, with more severe SMA types. In this thesis we therefore studied several characteristics of SMA’s natural history, with an emphasis on older children, adolescents and adult patients with SMA. This includes studies on survival, patterns of muscle strength and motor function decline, lung function, scoliosis development and associated need for scoliosis surgery. Additionally, we also studies possible involvement of tissues outside the nervous system, i.e. possible non-neuromuscular pathology in SMA. Finally, we studied fatigability, an important characteristic that impedes activities of daily life in many patients. We showed that pyridostigmine can improve patient’s fatigability and may be used as a safe, add-on therapy at low cost. The insights gained in this thesis have improved our insights into the natural history of SMA, may further improve care and counselling for patients and their caregivers, and may aid in further evaluations of (future) therapy efficacy.

Fatigability is frequently mentioned and considered as a highly debilitating impairment of daily life by many patients with SMA, but has nevertheless been given little priority for a long time. Until recently, clinical trials have been mainly focused on survival and early development of young infants with little understanding or sense of urgency with respect to fatigability despite this is an important problem for older patients. The results of these studies on fatigability in SMA will hopefully contribute to research and treatment of fatigability on three different levels. First, outcome measures are now available that can be used in clinical trials to assess efficacy in small heterogenous samples of children and adults with SMA. Secondly, we have demonstrated that fatigability is a highly prevalent additional dimension of physical impairment that requires attention and treatment. Third, we have demonstrated efficacy of a safe and low-cost treatment which can be used as an add-on therapy to genetic therapies or as an alternative for children and adults without access to expensive SMN-augmenting treatments. Fatigability in SMA is, however, a complex phenomenon of which the pathophysiological background, the impact on daily life and the optimal treatment will vary between patients. It is important to aim for a personalized approach in the near future, aiming to identify the main limiting factor, the most relevant outcome measures and the best treatment for each individual patient.

Progressive muscular atrophy (PMA) and multifocal motor neuropathy (MMN) share many clinical similarities. They are both characterized by progressive asymmetric muscle weakness with atrophy and fasciculations. Tendon reflexes are normally low or absent, although in some patients with MMN normal or even brisk reflexes in weakened muscles have been reported,1 making the clinical differentiation between PMA and MMN, but also early stages of amyotrophic lateral sclerosis (ALS), even harder. Most patients with PMA experience generalized weakness and develop respiratory failure as is seen in patients with ALS.2 A subset of PMA patients, however, have a slowly progressive disease course or segmental distribution of weakness in which symptoms remain limited to one limb,3,4 resembling the clinical phenotype of MMN. Although MMN and PMA are clinically much alike, the pathogenesis of both disorders is thought to be totally different. MMN on one hand belonging to the group of immune-mediated disorders of the peripheral nervous system such as Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP) and polyneuropathy associated with IgM monoclonal gammopathy. PMA on the other hand is considered a neurodegenerative disorder and part of the spectrum of motor neuron disorders, including ALS and primary lateral sclerosis (PLS), in which genetic vulnerability plays an important role. At the start of this research project, little was known about the contribution of inflammation to PMA pathogenesis and only few studies had addressed genetic heterogeneity in both PMA and MMN. Therefore, the main aim of this thesis was to investigate the contribution of genetic and inflammatory mechanisms in the pathogenesis of MMN and PMA, and to identify to what extent these pathophysiological processes overlap and differ between these two disorders and with ALS.

Polyneuropathy associated with IgM monoclonal gammopathy is a predominantly sensory, slowly progressive neuropathy for which treatment options are limited. In about 10% of patients antibodies against gangliosides or ganglioside complexes can be found. These antibodies do not always arise from a monoclonal B cell population. Different anti-ganglioside antibody specificities are associated with different clinical phenotypes. IL-6 and IL-10 serum concentrations differ between patients with neuropathy and controls and between those with or without anti-MAG antibodies. For both patients with anti-MAG or anti-ganglioside antibodies Fcγ-receptor polymorphisms may predict the response to treatment with rituximab, a monoclonal therapeutic antibody against CD20. Careful selection of patients for treatment with rituximab is necessary as it may lead to paradoxical deteriotation of the neuropathy during treatment.